Compounds and uses thereof

ABSTRACT

The present invention relates to compositions and methods for the treatment of BAF-related disorders, such as cancers and viral infections.

BACKGROUND

Disorders can be affected by the BAF complex. BRD9 is a component of theBAF complex. The present invention relates to useful compositions andmethods for the treatment of BAF complex-related disorders, such ascancer and infection.

SUMMARY

Bromodomain-containing protein 9 (BRD9) is a protein encoded by the BRD9gene on chromosome 5. BRD9 is a component of the BAF (BRG1- orBRM-associated factors) complex, a SWI/SNF ATPase chromatin remodelingcomplex, and belongs to family IV of the bromodomain-containingproteins. BRD9 is present in several SWI/SNF ATPase chromatin remodelingcomplexes and is upregulated in multiple cancer cell lines. Accordingly,agents that reduce the levels and/or activity of BRD9 may provide newmethods for the treatment of disease and disorders, such as cancer andinfection. The inventors have found that depleting BRD9 in cells resultsin the depletion of the SS18-SSX fusion protein in those cells. TheSS18-SSX fusion protein has been detected in more than 95% of synovialsarcoma tumors and is often the only cytogenetic abnormality in synovialsarcoma. Additionally, evidence suggests that the BAF complex isinvolved in cellular antiviral activities. Thus, agents that degradeBRD9 (e.g., compounds) are useful in the treatment of disorders (e.g.,cancers or infections) related to BAF, BRD9, and/or SS18-SSX.

The present disclosure features compounds and methods useful fortreating BAF-related disorders (e.g., cancer or infection).

In an aspect, the disclosure features a compound having the structure ofFormula I:

where

R¹ is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₂-C₆ alkenyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₁₀ carbocyclyl;

Z¹ is CR² or N;

R² is H, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉ heteroaryl;

X¹ is a bond, O, NR^(3a),

or CR^(4a)R^(5a);

X² is O, NR^(3b),

or CR^(4b)R^(5b);

X³ is O, NR^(3c),

or CR^(4c)R^(5c);

X⁴ is a bond, O, NR^(3d),

or CR^(4d)R^(5d);

X⁵ is O or NR^(3e) and X⁶ is CR^(4f)R^(5f), or X⁵ is CR^(4e)R^(5e) andX⁶ is O or NR^(3f);

X⁷ is O, NR^(3g), or CR^(4g)R^(5g);

X⁸ is O, NR^(3h), or CR^(4h)R^(5h);

each of R^(3a), R^(3b), R^(3c), and R^(3d) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3a) and R^(4b), R^(4a) and R^(3b), R^(4b) andR^(4a), R^(3b) and R^(4c), R^(4b) and R^(4c), R^(3c) and R^(4b), R^(3c)and R^(4d), R^(4c) and R^(4d), and/or R^(3d) and R^(4c), together withthe atoms to which each is attached, combine to form optionallysubstituted C₂-C₉ heterocyclyl;

each of R^(4a), R^(4b), R^(4c), and R^(4d) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, or optionally substituted amino, or R^(3a) andR^(4b), R^(4a) and R^(3b), R^(4b) and R^(4a), R^(3b) and R^(4c), R^(4b)and R^(4c), R^(3c) and R^(4b), R^(3c) and R^(4d), R^(4c) and R^(4d),and/or R^(3d) and R^(4c), together with the atoms to which each isattached, combine to form optionally substituted C₂-C₉ heterocyclyl;

each of R^(5a), R^(5b), R^(5c), and R^(5d) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino;

each of R^(3e), R^(3f), R^(3g), and R^(3h) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3e) and R^(4f) or R^(4e) and R^(3f), togetherwith the atoms to which each is attached, combine to form optionallysubstituted heterocyclycl;

each of R^(4e), R^(4f), R^(4g), and R^(4h) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3e) and R^(4f) or R^(4e) and R^(3f), togetherwith the atoms to which each is attached, combine to form optionallysubstituted heterocyclycl;

each of R^(5e), R^(5f), R^(5g), and R^(5h) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; and

G is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, or a pharmaceutically acceptable salt thereof.

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments, is

In another aspect, the disclosure features a compound having thestructure of Formula I:

where

R¹ is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₂-C₆ alkenyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₁₀ carbocyclyl;

Z¹ is CR² or N;

R² is H, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉ heteroaryl;

X¹ is a bond, O, NR^(3a), or CR^(4a)R^(5a);

X² is O, NR^(3b), or CR^(4b)R^(5b);

X³ is O, NR^(3c), or CR^(4c)R^(5c);

X⁴ is a bond, O, NR^(3d), or CR^(4d)R^(5d);

each of R^(3a), R^(3b), R^(3c), and R^(3d) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3a) and R^(4b), R^(4a) and R^(3b), R^(4b) andR^(4a), R^(3b) and R^(4c), R^(4b) and R^(4c), R^(3c) and R^(4b), R^(3c)and R^(4d), R^(4c) and R^(4d), and/or R^(3d) and R^(4c), together withthe atoms to which each is attached, combine to form optionallysubstituted C₂-C₉ heterocyclyl;

each of R^(4a), R^(4b), R^(4c), and R^(4d) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, or optionally substituted amino, or R^(3a) andR^(4b), R^(4a) and R^(3b), R^(4b) and R^(4a), R^(3b) and R^(4c), R^(4b)and R^(4c), R^(3c) and R^(4b), R^(3c) and R^(4d), R^(4c) and R^(4d),and/or R^(3d) and R^(4c), together with the atoms to which each isattached, combine to form optionally substituted C₂-C₉ heterocyclyl;

each of R^(5a), R^(5b), R^(5c), and R^(5d) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; and Gis optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, or optionally substitutedC₃-C₁₀ carbocyclyl. In some embodiments, R¹ is H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, or optionallysubstituted C₃-C₁₀ carbocyclyl. In some embodiments, R¹ is H, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₃-C₁₀ carbocyclyl.

In some embodiments, R¹ is H. In some embodiments, R¹ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R¹ is optionallysubstituted C₂-C₆ alkenyl. In some embodiments, R¹ is optionallysubstituted C₃-C₁₀ carbocyclyl.

In some embodiments, optionally substituted C₁-C₆ alkyl is C₁-C₆perfluoroalkyl.

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is H,

In some embodiments, R¹ is

In some embodiments, R¹ is H,

In some embodiments, R¹ is H,

In some embodiments, R¹ is H,

In some embodiments, R¹ is H or

In some embodiments, R¹ is H. In some embodiments, R¹ is

In some embodiments, Z¹ is CR². In some embodiments, Z¹ is N.

In some embodiments, R² is H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₃-C₁₀ carbocyclyl, or optionallysubstituted C₆-C₁₀ aryl.

In some embodiments, R² is H, halogen, or optionally substituted C₁-C₆alkyl.

In some embodiments, R² is H, F, or

In some embodiments, R² is H. In some embodiments, R² is F. In someembodiments, R² is

In some embodiments, X¹ is a bond, O, NR^(3a), or CR^(4a)R^(5a); X² isO, NR^(3b), or CR^(4b)R^(5b); X³ is O, NR^(3c), or CR^(4c)R^(5c); and X⁴is a bond, O, NR^(3d), or CR^(4d)R^(5d).

In some embodiments, X¹ is a bond. In some embodiments, X¹ is O,NR^(3a), or CR^(4a)R^(5a). In some embodiments, X¹ is O or NR^(3a). Insome embodiments, X¹ is NR^(3a) or CR^(4a)R^(5a) In some embodiments, X²is O or NR^(3b). In some embodiments, X² is CR^(4b)R^(5b). In someembodiments, X² is NR^(3b) or CR^(4b)R^(5b).

In some embodiments, X³ is O or NR^(3c). In some embodiments, X³ isCR^(4c)R^(5c). In some embodiments, X³ is NR^(3c) or CR^(4c)R^(5c).

In some embodiments, X⁴ is a bond. In some embodiments, X⁴ is O,NR^(3d), or CR^(4d)R^(5d). In some embodiments, X⁴ is O or NR^(3d). Insome embodiments, X⁴ is NR^(3d) or CR^(4d)R^(5d).

In some embodiments, X¹ is O, NR^(3a), or CR^(4a)R^(5a); X² is O,NR^(3b), or CR^(4b)R^(5b); X³ is O, NR^(3c), or CR^(4c)R^(5c); and X⁴ isO, NR^(3d), or CR^(4d)R^(5d).

In some embodiments, X¹ is CR^(4a)R^(5a); X² is NR^(3b); X³ isCR^(4c)R^(5c); and X⁴ is CR^(4d)R^(5d). In some embodiments, X¹ isCR^(4a)R^(5a); X² is CR^(4b)R^(5b); X³ is NR^(3c); and X⁴ isCR^(4d)R^(5d). In some embodiments, X¹ is O or NR^(3a); X² isCR^(4b)R^(5b); X³ is CR^(4c)R^(5c); and X⁴ is O or NR^(3d). In someembodiments, X¹ is a bond; X² is CR^(4b)R^(5b); X³ is O or NR^(3c); andX⁴ is CR^(4d)R^(5d). In some embodiments, X¹ is CR^(4a)R^(5a); X² isCR^(4b)R^(5b); X³ is CR^(4c)R^(5c); and X⁴ is CR^(4d)R^(5d). In someembodiments, X⁵ is NR^(3e) and X⁶ is CR^(4f)R^(5f).

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₁-C₆ acyl,optionally substituted sulfone, or optionally substituted sulfonamide.In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted sulfone, oroptionally substituted sulfonamide. In some embodiments, each of R^(3a),R^(3b), R^(3c), and R^(3d) is, independently, H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ acyl, optionally substitutedsulfone, or optionally substituted sulfonamide. In some embodiments,each of R^(3a), R^(3b), R^(3c), and R^(3d) is, independently, H,optionally substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆acyl.

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₁-C₆ acyl,optionally substituted sulfone, or optionally substituted sulfonamide.In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ acyl, optionally substituted sulfone, or optionallysubstituted sulfonamide.

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, or optionally substituted C₁-C₆ acyl. Insome embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, optionally substituted C₁-C₆ alkyl or optionallysubstituted C₁-C₆ heteroalkyl. In some embodiments, each of R^(3a),R^(3b), R^(3c), and R^(3d) is, independently, optionally substitutedC₁-C₆ alkyl or optionally substituted C₁-C₆ acyl. In some embodiments,each of R^(3a), R^(3b), R^(3c), and R^(3d) is, independently, optionallysubstituted C₁-C₆ acyl. In some embodiments, each of R^(3a), R^(3b),R^(3c), and R^(3d) is, independently, optionally substituted sulfone oroptionally substituted sulfonamide.

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, H, optionally substituted C₁-C₆ alkyl,

where

R⁵ is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, oroptionally substituted C₆-C₁₀ aryl;

W¹ is O or S;

W² is NR⁷ or O;

R⁷ is H, optionally substituted C₁-C₆ alkyl, or optionally substitutedC₁-C₆ heteroalkyl;

R⁸ is optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, or optionallysubstituted C₆-C₁₀ aryl; and

R⁹ is H, optionally substituted C₁-C₆ alkyl, or optionally substitutedC₁-C₆ heteroalkyl.

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, C₁-C₆ alkyl,

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, C₁-C₆ alkyl. In some embodiments, each of R^(3a), R^(3b),R^(3c), and R^(3d) is, independently,

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently,

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently,

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently,

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, H, optionally substituted C₁-C₆ alkyl,

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, H, C₁-C₆ alkyl,

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, H, C₁-C₆ alkyl, or

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, C₁-C₆ alkyl

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, H, methyl, or

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, optionally substituted C₁-C₆ alkyl.

In some embodiments, each of R^(4a), R^(4b), R^(4c), and R^(4d) is,independently, H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₁-C₆ acyl,optionally substituted sulfone, or optionally substituted sulfonamide.In some embodiments, each of R^(4a), R^(4b), R^(4c), and R^(4d) is,independently, H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted sulfone, oroptionally substituted sulfonamide. In some embodiments, each of R^(4a),R^(4b), R^(4c), and R^(4d) is H. In some embodiments, each of R^(4a),R^(4b), R^(4c), and R^(4d) is, independently, H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ acyl, optionally substitutedsulfone, or optionally substituted sulfonamide. In some embodiments,each of R^(4a), R^(4b), R^(4c), and R^(4d) is, independently, H,optionally substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆acyl.

In some embodiments, each of R^(4a), R^(4b), R^(4c), and R^(4d) is,independently, H, optionally substituted C₁-C₆ alkyl,

where

R⁶ is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, oroptionally substituted C₆-C₁₀ aryl;

W¹ is O or S;

W² is NR⁷ or O;

R⁷ is H, optionally substituted C₁-C₆ alkyl, or optionally substitutedC₁-C₆ heteroalkyl;

R⁸ is optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, or optionallysubstituted C₆-C₁₀ aryl; and

R⁹ is H, optionally substituted C₁-C₆ alkyl, or optionally substitutedC₁-C₆ heteroalkyl.

In some embodiments, each of R^(4a), R^(4b), R^(4c), and R^(4d) is,independently, H, optionally substituted C₁-C₆ alkyl,

In some embodiments, each of R^(4a), R^(4b), R^(4c), and R^(4d) is,independently, H or optionally substituted C₁-C₆ alkyl. In someembodiments, each of R^(4a), R^(4b), R^(4c), and R^(4d) is,independently, H.

In some embodiments, W¹ is O. In some embodiments, W¹ is S.

In some embodiments, W² is O. In some embodiments, W² is NR⁷.

In some embodiments, R⁶ is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, or optionally substitutedC₃-C₁₀ carbocyclyl. In some embodiments, R⁶ is H, optionally substitutedC₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl. In someembodiments, R⁶ is H, optionally substituted C₃-C₁₀ carbocyclyl, oroptionally substituted C₆-C₁₀ aryl. In some embodiments, R⁶ isoptionally substituted C₁-C₆ alkyl or optionally substituted C₁-C₆heteroalkyl. In some embodiments, R⁶ is optionally substituted C₃-C₁₀carbocyclyl or optionally substituted C₆-C₁₀ aryl

In some embodiments, R⁶ is H, methyl, ethyl

In some embodiments, R⁶ is H. In some embodiments, R⁶ is methyl, ethyl,

In some embodiments, R⁶ is

In some embodiments, R⁶ is H, methyl, ethyl,

In some embodiments, R⁷ is H or optionally substituted C₁-C₆ alkyl. Insome embodiments, R⁷ is H or methyl.

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, H, methyl,

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, H, methyl,

In some embodiments, R^(3a) is H, methyl,

In some embodiments, R^(3b) is H, methyl,

In some embodiments, R^(3c) is H, methyl,

In some embodiments, R^(3d) is H, methyl,

In some embodiments, R^(3a) and R^(4b), R^(4a) and R^(3b), R^(4b) andR^(4a), R^(3b) and R^(4c), R^(4b) and R^(4c), R^(3c) and

R^(4b), R^(3c) and R^(4d), R^(4c) and R^(4d), and/or R^(3d) and R^(4c),together with the atoms to which each is attached, combine to formoptionally substituted C₂-C₉ heterocyclyl.

In some embodiments, R^(3a) and R^(4b), R^(4b) and R^(4a), R^(4b) andR^(4c), R^(3c) and R^(4b), R^(3c) and R^(4d), and/or R^(3d) and R^(4c),together with the atoms to which each is attached, combine to formoptionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(5a), R^(5b), R^(5c), and R^(5d) is,independently, H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl. In some embodiments, each of R^(5a),R^(5b), R^(5c), and R^(5d) is H.

In some embodiments, each of R^(3e), R^(3f), R^(3g), and R^(3h) is,independently, H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₁-C₆ acyl,optionally substituted sulfone, or optionally substituted sulfonamide.

In some embodiments, each of R^(4e), R^(4f), R^(4g), and R^(4h) is,independently, H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₁-C₆ acyl,optionally substituted sulfone, or optionally substituted sulfonamide.

In some embodiments, each of R^(5e), R^(5f), R^(5g), and R^(5h) is,independently, H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl. In some embodiments, each of R^(5e),R^(5f), R^(5g), and R^(5h) is H.

In some embodiments, G is optionally substituted C₃-C₁₀ carbocyclyl oroptionally substituted C₂-C₉ heterocyclyl. In some embodiments, G isoptionally substituted C₆-C₁₀ aryl or optionally substituted C₂-C₉heteroaryl.

In some embodiments, G is optionally substituted C₃-C₁₀ carbocyclyl. Insome embodiments, G is optionally substituted C₆-C₁₀ aryl. In someembodiments, G is optionally substituted C₂-C₉ heterocyclyl. In someembodiments, G is optionally substituted C₂-C₉ heteroaryl.

In some embodiments, G is

where

each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5) is, independently, H,halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) and R^(G4), and/or R^(G4)and R^(G5), together with the carbon atoms to which each is attached,combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₆-C₁₀aryl, optionally substituted C₃-C₁₀ carbocyclyl, optionally substitutedC₂-C₉ heteroaryl, or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl; or R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heteroaryl or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, F, Cl,

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, F,

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, F, Cl,

In some embodiments, R^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is

and R^(G5) is H. In some embodiments, R^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is H; and R^(G5) is

In some embodiments, R^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is Cl or F; and R^(G5) is H. In some embodiments, R^(G1) is H;R^(G2) is

R^(G3) is

R^(G4) is H; and R^(G5) is H. In some embodiments, R^(G1) is H; R^(G2)is

R^(G3) is

R^(G4) is

and R^(G5) is H.

In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heteroaryl or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heterocyclyl. In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3),R^(G3) and R^(G4), and/or R^(G4) and R^(G5), together with the carbonatoms to which each is attached, combine to form optionally substitutedC₂-C₉ heteroaryl.

In some embodiments, G is

where R^(G6) is H or optionally substituted C₁-C₆ alkyl. In someembodiments, G is

where R^(G6) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heterocyclyl or optionally substituted C₂-C₉ heteroaryl.

In some embodiments, G is

where R^(G6) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(G6) is H,

In some embodiments, R^(G6) is H or

In some embodiments, R^(G6) is H.

In some embodiments, R^(G1) is H, F,

In some embodiments, R^(G1) is H.

In some embodiments, R^(G2) is H, F,

In some embodiments, R^(G2) is H.

In some embodiments, R^(G3) is H, F,

In some embodiments, R^(G3) is H.

In some embodiments, R^(G4) is H, F,

In some embodiments, R^(G4) is H.

In some embodiments, R^(G5) is H, F,

In some embodiments, R^(G5) is H.

In some embodiments, one or more of R^(G1), R^(G2), R^(G3), R^(G4), andR^(G5) is H. In some embodiments, two or more of R^(G1), R^(G2), R^(G3),R^(G4), and R^(G5) is H. In some embodiments, three or more of R^(G1),R^(G2), R^(G3), R^(G4), and R^(G5) is H. In some embodiments, each ofR^(G1), R^(G2), R^(G3), R^(G4), and R^(G5) is H.

In some embodiments, G is

where

each of R^(G7), R^(G8), R^(G9), R^(G10), and R^(G11) is, independently,H, halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G7) and R^(G8), R^(G8) and R^(G9), R^(G9) and R^(G10), and/or R^(G10)and R^(G11), together with the carbon atoms to which each is attached,combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxyl, thiol, or optionally substituted amino;or R^(G7) and R^(G8), R^(G8) and R^(G9), R^(G9) and R^(G10), and/orR^(G10) and R^(G11), together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl; or R^(G7) and R^(G8), R^(G8) and R^(G9), R^(G9) andR^(G10), and/or R^(G10) and R^(G11), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₆-C₁₀aryl, optionally substituted C₃-C₁₀ carbocyclyl, optionally substitutedC₂-C₉ heteroaryl, or C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, F, Cl,

In some embodiments, R^(G8) is

In some embodiments, G is

In some embodiments, R^(G7) is H; R^(G8) is

R^(G9) is H; and R^(G11) is H.

In some embodiments, G is

where

each of R^(G12), R^(G13), and R^(G14) is, independently, H, halogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G12) and R^(G14), together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G12), R^(G13), and R^(G14) is,independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; orR^(G12) and R^(G14), together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, the structure of Formula I has the structure ofFormula Ia:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula I has the structure ofFormula Ib:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula I has the structure ofFormula Ic:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula I has the structure ofFormula Id:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula I has the structure ofFormula Ie:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula I has the structure ofFormula If:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula I has the structure ofFormula Ig:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula I has the structure ofFormula Ih:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula I has the structure ofFormula Ii:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula I has the structure ofFormula Ij:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure of any one ofcompounds B1-B21 in Table 1A, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound has the structure of any oneof compounds B22-B24 in Table 1B, or a pharmaceutically acceptable saltthereof.

In an aspect, the disclosure features a compound having the structure ofany one of compounds B1-B21 in Table 1A, or a pharmaceuticallyacceptable salt thereof.

In another aspect, the disclosure features a compound having thestructure of any one of compounds B22-B24 in Table 1B, or apharmaceutically acceptable salt thereof.

TABLE 1A Compounds B1-B21 of the Disclosure Compound No. Structure B1 

B2 

B3 

B4 

B5 

B6 

B7 

B8 

B9 

B10

B11

B12

B13

B14

B15

B16

B17

B18

B19

B20

B21

TABLE 1B Compounds B22-B24 of the Disclosure Compound No. Structure  B22

B23

B24

In another aspect, the disclosure features a compound having thestructure of Formula II:

A-L-B   Formula II,

where

B is a degradation moiety,

L is a linker, and

A has the structure of Formula III:

where

R¹ is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₂-C₆ alkenyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₁₀ carbocyclyl;

Z¹ is CR² or N;

R² is H, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉ heteroaryl;

X¹′ is a bond, O, NR^(3a)′, or CR^(4a)′R^(5a)′;

X²′ is O, NR^(3b)′, or CR^(4b)′R^(5b)′;

X³′ is O, NR^(3c)′, or CR^(4c)′R^(5c)′;

X⁴′ is a bond, O, NR^(3d)′, or CR^(4d)′R^(5d)′;

X⁵′ is O, NR^(3e)′, or CR^(4e)′R^(5e)′;

X⁶′ is O, NR^(3f)′, or CR^(4f)′R^(5f)′;

X⁷′ is O, NR^(3g)′, or CR^(4g)′R^(5g)′;

each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is, independently, H,

halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3a)′ and R^(4b)′, R^(4a)′ and R^(3b)′, R^(4b)′and R^(4a)′, R^(3b)′ and R^(4c)′, R^(4b)′ and R^(4c)′, R^(3c)′ andR^(4b)′, R^(3c)′ and R^(4d)′, R^(4c)′ and R^(4d)′, and/or R^(3d)′ andR^(4c)′, together with the atoms to which each is attached, combine toform optionally substituted C₂-C₉ heterocyclyl;

R³′ is absent, optionally substituted C₁-C₆ alkylene, optionallysubstituted C₁-C₆ heteroalkylene, optionally substituted C₃-C₁₀carbocyclylene, optionally substituted C₂-C₉ heterocyclylene, optionallysubstituted C₆-C₁₀ arylene, optionally substituted C₂-C₉ heteroarylene,optionally substituted C₂-C₆ alkenylene, optionally substituted C₂-C₆heteroalkenylene, optionally substituted sulfone, optionally substitutedsulfonamide, or optionally substituted amino;

each of R^(4a)′, R^(4b)′, R^(4c)′, and R^(4d)′ is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, thiol, optionally substituted sulfone, or optionallysubstituted amino, or R^(3a)′ and R^(4b)′, R^(4a)′ and R^(3b)′, R^(4b)′and R^(4a)′, R^(3b)′ and R^(4c)′, R^(4b)′ and R^(4c)′, R^(3c)′ andR^(4b)′, R^(3c)′ and R^(4d)′, R^(4c)′ and R^(4d)′, and/or R^(3d)′ andR^(4c)′, together with the atoms to which each is attached, combine toform optionally substituted C₂-C₉ heterocyclyl;

each of R^(5a)′, R^(5b)′, R^(5′), and R^(5d)′ is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino;

each of R^(3e)′, R^(3f)′, and R^(3g)′ is, independently, H,

halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3e) and R^(4f) or R^(4e) and R^(3f), togetherwith the atoms to which each is attached, combine to form optionallysubstituted heterocyclycl;

each of R^(4e)′, R^(4f)′, and R^(4g)′ is, independently, H, halogen,hydroxyl, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted C₁-C₆ acyl, thiol, optionally substituted sulfone,optionally substituted sulfonamide, or optionally substituted amino, orR^(3e)′ and R^(4f)′ or R^(4e)′ and R^(3f)′, together with the atoms towhich each is attached, combine to form optionally substitutedheterocyclycl;

each of R^(5e)′, R^(5f)′, and R^(5g)′ is, independently, H, halogen,hydroxyl, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, hydroxyl, thiol, oroptionally substituted amino;

G″ is

optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl;

G′ is optionally substituted C₃-C₁₀ carbocyclylene, C₂-C₉heterocyclylene, optionally substituted C₆-C₁₀ arylene, or optionallysubstituted C₂-C₉ heteroarylene; and

A¹ is a bond between A and the linker,

where one of R^(3a)′, R^(3b)′, R^(3c)′, R^(3d)′, R^(3e)′, R^(3f)′, andR^(3g)′ is

or G is

or a pharmaceutically acceptable salt thereof.

In some embodiments,

In some embodiments,

is

In some embodiments,

In another aspect, the disclosure features a compound having thestructure of Formula II:

A-L-B   Formula II,

where

B is a degradation moiety,

L is a linker, and

A has the structure of Formula III:

where

R¹ is, independently, H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₁₀ carbocyclyl;

Z¹ is CR² or N;

R² is H, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉ heteroaryl;

X¹′ is a bond, O, NR^(3a)′, or CR^(4a)′R^(5a)′;

X²′ is O, NR^(3b)′, or CR^(4b)′R^(5b)′;

X³′ is O, NR^(3c)′, or CR^(4c)′R^(5c)′;

X⁴′ is a bond, O, NR^(3d)′, or CR^(4d)′R^(5d)′;

each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is, independently, H,

halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3a)′ and R^(4b), R^(4a)′ and R^(3b)′, R^(4b)′and R^(4a)′, R^(3b)′ and R^(4c)′, R^(4b)′ and R^(4c)′, R^(3c)′ andR^(4b)′, R^(3c)′ and R^(4d)′, R^(4c)′ and R^(4d)′, and/or R^(3d)′ andR^(4c)′, together with the atoms to which each is attached, combine toform optionally substituted C₂-C₉ heterocyclyl;

R³′ is absent, optionally substituted C₁-C₆ alkylene, optionallysubstituted C₁-C₆ heteroalkylene, optionally substituted C₃-C₁₀carbocyclylene, optionally substituted C₂-C₉ heterocyclylene, optionallysubstituted C₆-C₁₀ arylene, optionally substituted C₂-C₉ heteroarylene,optionally substituted C₂-C₆ alkenylene, optionally substituted C₂-C₆heteroalkenylene, optionally substituted sulfone, optionally substitutedsulfonamide, or optionally substituted amino;

each of R^(4a)′, R^(4b)′, R^(4c)′, and R^(4d)′ is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, thiol, optionally substituted sulfone, or optionallysubstituted amino, or R^(3a)′ and R^(4b), R^(4a)′ and R^(3b)′, R^(4b)′and R^(4a)′, R^(3b)′ and R^(4c)′, R^(4b)′ and R^(4c)′, R^(3c)′ andR^(4b)′, R^(3c)′ and R^(4d)′, R^(4c)′ and R^(4d)′, and/or R^(3d)′ andR^(4c)′, together with the atoms to which each is attached, combine toform optionally substituted C₂-C₉ heterocyclyl;

each of R^(5a)′, R^(5b)′, R^(5c)′, and R^(5d)′ is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino;

G″ is

optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl;

G′ is optionally substituted C₃-C₁₀ carbocyclylene, C₂-C₉heterocyclylene, optionally substituted C₆-C₁₀ arylene, or optionallysubstituted C₂-C₉ heteroarylene; and

A¹ is a bond between A and the linker,

where one of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is

or G is

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, or optionally substitutedC₃-C₁₀ carbocyclyl. In some embodiments, R¹ is H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, or optionallysubstituted C₃-C₁₀ carbocyclyl. In some embodiments, R¹ is H, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₃-C₁₀ carbocyclyl.

In some embodiments, R¹ is H. In some embodiments, R¹ is optionallysubstituted C₁-C₆ alkyl. In some embodiments, R¹ is optionallysubstituted C₂-C₆ alkenyl. In some embodiments, R¹ is optionallysubstituted C₃-C₁₀ carbocyclyl.

In some embodiments, optionally substituted C₁-C₆ alkyl is C₁-C₆perfluoroalkyl.

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is H,

In some embodiments, R¹ is

In some embodiments, R¹ is H,

In some embodiments, R¹ is H,

In some embodiments, R¹ is H,

In some embodiments, R¹ is H or

In some embodiments, R¹ is H. In some embodiments, R¹ is

In some embodiments, Z¹ is CR². In some embodiments, Z¹ is N.

In some embodiments, R² is H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₃-C₁₀ carbocyclyl, or optionallysubstituted C₆-C₁₀ aryl.

In some embodiments, R² is H, halogen, or optionally substituted C₁-C₆alkyl.

In some embodiments, R² is H, F, or

In some embodiments, R² is H. In some embodiments, R² is F. In someembodiments, R² is

In some embodiments, X¹′ is a bond. In some embodiments, X¹ is O,NR^(3a)′, or CR^(4a)′R^(5a)′. In some embodiments, X¹′ is O or NR^(3a)′.In some embodiments, X¹′ is NR^(3a)′ or CR^(4a)′R^(5a)′.

In some embodiments, X²′ is O or NR^(3b)′. In some embodiments, X²′ isCR^(4b)′R^(5b)′. In some embodiments, X²′ is NR^(3b)′ orCR^(4b)′R^(5b)′.

In some embodiments, X³′ is O or NR^(3c)′. In some embodiments, X³′ isCR^(4c)′R^(5c)′. In some embodiments, X³′ is NR^(3c)′ orCR^(4c)′R^(5c)′.

In some embodiments, X⁴′ is a bond. In some embodiments, X⁴′ is O,NR^(3d)′, or CR^(4d)′R^(5d)′. In some embodiments, X⁴′ is O or NR^(3d)′.In some embodiments, X⁴′ is NR^(3d)′ or CR^(4d)′R^(5d)′.

In some embodiments, X¹′ is O, NR^(3a)′, or CR^(4a)′R^(5a)′; X²′ is O,NR^(3b)′, or CR^(4b)′R^(5b)′; X³′ is O, NR^(3c)′, or CR^(4c)′R^(5c)′;and X⁴′ is O, NR^(3d)′, or CR^(4d)′R^(5d)′.

In some embodiments, X¹′ is CR^(4a)‘R^(5a)’; X²′ is NR^(3b)′; X³′ isCR^(4c)′R^(5c)′; and X⁴′ is CR^(4d)′R^(5d)′.

In some embodiments, X¹′ is CR^(4a)′R^(5a)′; X²′ is CR^(4b)′R^(5b)′; X³′is NR^(3c)′; and X⁴′ is CR^(4d)′R^(5d)′.

In some embodiments, X¹′ is O or NR^(3a)′; X²′ is CR^(4b)′R^(5b)′; X³′is CR^(4c)′R^(5c)′; and X⁴′ is O or NR^(3d)′.

In some embodiments, X¹′ is a bond; X²′ is CR^(4b)′R^(5b)′; X³′ is O orNR^(3c)′; and X⁴′ is CR^(4d)′R^(5d)′.

In some embodiments, X¹′ is CR^(4a)′R^(5a)′; X²′ is CR^(4b)′R^(5b)′; X³′is CR^(4c)′R^(5c)′; and X⁴′ is CR^(4d)′R^(5d)′.

In some embodiments, X⁵′ is CR^(4e)′R^(5e)′ and X⁶′ is NR^(3f)′.

In some embodiments, each of R^(3a)′, R^(3b′), R^(3′), and R^(3d)′ is,independently, H,

optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₁-C₆ acyl, optionally substitutedsulfone, or optionally substituted sulfonamide. In some embodiments,each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is, independently, H,

optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted sulfone, or optionally substitutedsulfonamide. In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, andR^(3d)′ is, independently, H,

optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ acyl,optionally substituted sulfone, or optionally substituted sulfonamide.In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H,

optionally substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆acyl.

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently,

optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₁-C₆ acyl, optionally substitutedsulfone, or optionally substituted sulfonamide. In some embodiments,each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is, independently,

optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ acyl,optionally substituted sulfone, or optionally substituted sulfonamide.

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently,

optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, or optionally substituted C₁-C₆ acyl. In some embodiments,each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is, independently,

optionally substituted C₁-C₆ alkyl or optionally substituted C₁-C₆heteroalkyl. In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, andR^(3d)′ is, independently,

optionally substituted C₁-C₆ alkyl or optionally substituted C₁-C₆ acyl.In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently,

or optionally substituted C₁-C₆ acyl. In some embodiments, each ofR^(3a)′, R^(3′), R^(3c)′, and R^(3d)′ is, independently,

optionally substituted sulfone, or optionally substituted sulfonamide.

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H,

optionally substituted C₁-C₆ alkyl,

where

R⁶ is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, oroptionally substituted C₆-C₁₀ aryl;

W¹ is O or S;

W² is NR⁷ or O;

R⁷ is H, optionally substituted C₁-C₆ alkyl, or optionally substitutedC₁-C₆ heteroalkyl;

R⁸ is optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, or optionallysubstituted C₆-C₁₀ aryl; and

R⁹ is H, optionally substituted C₁-C₆ alkyl, or optionally substitutedC₁-C₆ heteroalkyl.

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently,

C₁-C₆ alkyl,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently,

or C₁-C₆ alkyl. In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′,and R^(3d)′ is, independently

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d) is,independently,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H,

optionally substituted C₁-C₆ alkyl,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H,

C₁-C₆ alkyl,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H,

C₁-C₆ alkyl, or

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently,

C₁-C₆ alkyl, or

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H,

methyl, or

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently

or optionally substituted C₁-C₆ alkyl.

In some embodiments, each of R^(4a)′, R^(4b)′, R^(4c)′, and R^(4d)′ is,independently, H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₁-C₆ acyl,optionally substituted sulfone, or optionally substituted sulfonamide.In some embodiments, each of R^(4a)′, R^(4b)′, R^(4c)′, and R^(4d)′ is,independently, H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted sulfone, oroptionally substituted sulfonamide. In some embodiments, each of R^(4a),R^(4b)′, R^(4c)′, and R^(4d)′ is H. In some embodiments, each ofR^(4a)′, R^(4b)′, R^(4c)′, and R^(4d)′ is, independently, H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ acyl, optionallysubstituted sulfone, or optionally substituted sulfonamide. In someembodiments, each of R^(4a)′, R^(4b)′, R^(4c)′, and R^(4d)′ is,independently, H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ acyl.

In some embodiments, each of R^(4a)′, R^(4b)′, R^(4c)′, and R^(4d)′ is,independently, H, optionally substituted C₁-C₆ alkyl,

where

R⁶ is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, oroptionally substituted C₆-C₁₀ aryl;

W¹ is O or S;

W² is NR⁷ or O;

R⁷ is H, optionally substituted C₁-C₆ alkyl, or optionally substitutedC₁-C₆ heteroalkyl;

R⁸ is optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, or optionallysubstituted C₆-C₁₀ aryl; and

R⁹ is H, optionally substituted C₁-C₆ alkyl, or optionally substitutedC₁-C₆ heteroalkyl.

In some embodiments, each of R^(4a)′, R^(4b)′, R^(4c)′, and R^(4d)′ is,independently, H, optionally substituted C₁-C₆ alkyl,

In some embodiments, each of R^(4a)′, R^(4b)′, R^(4c)′, and R^(4d)′ is,independently, H or optionally substituted C₁-C₆ alkyl. In someembodiments, each of R^(4a)′, R^(4b)′, R^(4c)′, and R^(4d)′ is,independently, H.

In some embodiments, W¹ is O. In some embodiments, W¹ is S.

In some embodiments, W² is O. In some embodiments, W² is NR⁷.

In some embodiments, R⁶ is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, or optionally substitutedC₃-C₁₀ carbocyclyl. In some embodiments, R⁶ is H, optionally substitutedC₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl. In someembodiments, R⁶ is H, optionally substituted C₃-C₁₀ carbocyclyl, oroptionally substituted C₆-C₁₀ aryl. In some embodiments, R⁶ isoptionally substituted C₁-C₆ alkyl or optionally substituted C₁-C₆heteroalkyl. In some embodiments, R⁶ is optionally substituted C₃-C₁₀carbocyclyl or optionally substituted C₆-C₁₀ aryl

In some embodiments, R⁶ is H, methyl, ethyl,

In some embodiments, R⁶ is H or

In some embodiments, R⁶ is methyl, ethyl,

In some embodiments, R⁶ is or

In some embodiments, R⁶ is H. In some embodiments, R⁶ is H, methyl,ethyl,

In some embodiments, R⁷ is H or optionally substituted C₁-C₆ alkyl. Insome embodiments, R⁷ is H or methyl.

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H,

methyl,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H,

methyl,

In some embodiments, R^(3a)′ is H,

methyl

In some embodiments, R^(3b)′ is H,

methyl,

In some embodiments, R^(3c)′ is H

methyl,

In some embodiments, R^(3d)′ is H,

methyl,

In some embodiments, one of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is

In some embodiments, R^(3b)′ is

In some embodiments, R^(3c)′ is

In some embodiments, R³′ is absent.

In some embodiments, R^(3a)′ and R^(4b)′, R^(4a)′ and R^(3b)′, R^(4b)′and R^(4a)′, R^(3b)′ and R^(4c)′, R^(4b)′ and R^(4c)′, R^(3c)′ andR^(4b)′, R^(3c)′ and R^(4d)′, R^(4c)′ and R^(4d)′, and/or R^(3d)′ andR^(4c)′, together with the atoms to which each is attached, combine toform optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, R^(3a)′ and R^(4b)′, R^(4a)′ and R^(3b)′, R^(3b)′and R^(4′), R^(4b)′ and R^(3′), R^(3c)′ and R^(4d), and/or R^(4c)′ andR^(3d)′, together with the atoms to which each is attached, combine toform optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(5a), R^(5b), R^(5c), and R^(5d) is,independently, H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl. In some embodiments, each of R^(5a),R^(5b), R^(5c), and R^(5d) is H.

In some embodiments, each of R^(3e)′, R^(3f)′, and R^(3g)′ is,independently H,

optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₁-C₆ acyl, optionally substitutedsulfone, or optionally substituted sulfonamide.

In some embodiments, each of R^(4e)′, R^(4f)′, and R^(4g)′ is,independently, H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₁-C₆ acyl,optionally substituted sulfone, or optionally substituted sulfonamide.

In some embodiments, each of R^(5e)′, R^(5f)′, and R^(5g)′ is,independently, H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl. In some embodiments, each of R^(5e)′,R^(5f)′, and R^(5g)′ is H.

In some embodiments, G″ is optionally substituted C₃-C₁₀ carbocyclyl oroptionally substituted C₂-C₉ heterocyclyl. In some embodiments, G″ isoptionally substituted C₆-C₁₀ aryl or optionally substituted C₂-C₉heteroaryl.

In some embodiments, G″ is optionally substituted C₃-C₁₀ carbocyclyl. Insome embodiments, G is optionally substituted C₆-C₁₀ aryl. In someembodiments, G is optionally substituted C₂-C₉ heterocyclyl. In someembodiments, G″ is optionally substituted C₂-C₉ heteroaryl.

In some embodiments, G″ is

where

each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5) is, independently, H,halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) and R^(G4), and/or R^(G4)and R^(G5), together with the carbon atoms to which each is attached,combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₆-C₁₀aryl, optionally substituted C₃-C₁₀ carbocyclyl, optionally substitutedC₂-C₉ heteroaryl, or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl; or R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heteroaryl or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, F, Cl,

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4) and R^(G5)is, independently, H, F

In some embodiments, each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5)is, independently, H, F, Cl,

In some embodiments, R^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is

and R^(G5) is H. In some embodiments, R^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is H; and R^(G5) is

In some embodiments, R^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is Cl or F; and R^(G5) is H. In some embodiments, R^(G1) is H;R^(G2) is

R^(G3) is

R^(G4) is H; and R^(G5) is H. In some embodiments, R^(G1) is H; R^(G2)is

R^(G3) is

R^(G4) is

and R^(G5) is H.

In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heteroaryl or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heterocyclyl. In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3),R^(G3) and R^(G4), and/or R^(G4) and R^(G5), together with the carbonatoms to which each is attached, combine to form optionally substitutedC₂-C₉ heteroaryl.

In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heterocyclyl. In some embodiments, R^(G1) and R^(G2), R^(G2) and R^(G3),R^(G3) and R^(G4), and/or R^(G4) and R^(G5), together with the carbonatoms to which each is attached, combine to form optionally substitutedC₂-C₉ heteroaryl.

In some embodiments, G″ is

where R^(G6) is H or optionally substituted C₁-C₆ alkyl. In someembodiments, G″ is

where R^(G6) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, G″ is

where R^(G6) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(G6) is H,

In some embodiments, R^(G6) is H or

In some embodiments, R^(G6) is H.

In some embodiments, R^(G1) is H, F,

In some embodiments, R^(G1) is H.

In some embodiments, R^(G2) is H, F,

In some embodiments, R^(G2) is H.

In some embodiments, R^(G3) is H, F,

In some embodiments, R^(G3) is H.

In some embodiments, R^(G4) is H, F,

In some embodiments, R^(G4) is H.

In some embodiments, R^(G5) is H, F,

In some embodiments, R^(G5) is H.

In some embodiments, one or more of R^(G1), R^(G2), R^(G3), R^(G4), andR^(G5) is H. In some embodiments, two or more of R^(G1), R^(G2), R^(G3),R^(G4), and R^(G5) is H. In some embodiments, three or more of R^(G1),R^(G2), R^(G3), R^(G4), and R^(G5) is H. In some embodiments, each ofR^(G1), R^(G2), R^(G3), R^(G4), and R^(G5) is H.

In some embodiments, G″ is

where

each of R^(G7), R^(G8), R^(G9), R^(G10), and R^(G11) is, independently,H, halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G7) and R^(G8), R^(G8) and R^(G9), R^(G9) and R^(G10), and/or R^(G10)and R^(G11), together with the carbon atoms to which each is attached,combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxyl, thiol, or optionally substituted amino;or R^(G7) and R^(G8), R^(G8) and R^(G9), R^(G9) and R^(G10), and/orR^(G10) and R^(G11), together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl; or R^(G7) and R^(G8), R^(G8) and R^(G9), R^(G9) andR^(G10), and/or R^(G10) and R^(G11), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₆-C₁₀aryl, optionally substituted C₃-C₁₀ carbocyclyl, optionally substitutedC₂-C₉ heteroaryl, or C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.

In some embodiments, each of R^(G7), R^(G8), R^(G9), R^(G10), andR^(G11) is, independently, H, F, Cl,

In some embodiments, R^(G8) is

In some embodiments, G″ is

In some embodiments, R^(G7) is H; R^(G8) is

R^(G9) is H; and R^(G11) is H.

In some embodiments, G″ is

where

each of R^(G12), R^(G13), and R^(G14) is, independently, H, halogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G12) and R^(G14), together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each of R^(G12), R^(G13), and R^(G14) is,independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; orR^(G12) and R^(G14), together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, G″ is

In some embodiments, G′ is optionally substituted C₃-C₁₀ carbocyclyleneor optionally substituted C₂-C₉ heterocyclylene. In some embodiments, G′is optionally substituted C₆-C₁₀ arylene or optionally substituted C₂-C₉heteroarylene.

In some embodiments, G′ is optionally substituted C₃-C₁₀ carbocyclylene.In some embodiments, G′ is optionally substituted C₆-C₁₀ arylene. Insome embodiments, G′ is optionally substituted C₂-C₉ heterocyclylene. Insome embodiments, G′ is optionally substituted C₂-C₉ heteroarylene.

In some embodiments, G′ is

where

each of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, and R^(G5)′ is,independently, H, A¹, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G1)′ and R^(G2)′, R^(G2)′ and R^(G3)′, R^(G3)′and R^(G4)′, and/or R^(G4)′ and R^(G5)′, together with the carbon atomsto which each is attached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or optionallysubstituted C₂-C₉ heterocyclyl, any of which is optionally substitutedwith A¹, where one of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, and R^(G5)′ isA¹, or

is substituted with A¹.

In some embodiments, each of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, andR^(G5)′ is, independently, H, A¹, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl,optionally substituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, oroptionally substituted amino; or R^(G1)′ and R^(G2)′, R^(G2)′ andR^(G3)′, R^(G3)′ and R^(G4)′, and/or R^(G4)′ and R^(G5)′, together withthe carbon atoms to which each is attached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or optionallysubstituted C₂-C₉ heterocyclyl, any of which is optionally substitutedwith A¹, where one of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, and R^(G5)′ isA¹, or

is substituted with A¹.

In some embodiments, each of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, andR^(G5)′ is, independently, H, A¹, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl; or R^(G1)′ and R^(G2)′, R^(G2)′ and R^(G3)′, R^(G3)′ andR^(G4)′, and/or R^(G4)′ and R^(G5)′, together with the carbon atoms towhich each is attached, combine to form

; and

is optionally substituted C₂-C₉ heteroaryl or optionally substitutedC₂-C₉ heterocyclyl, any of which is optionally substituted with A¹,where one of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, and R^(G5)′ is A¹, or

is substituted with A¹.

In some embodiments, each of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, andR^(G5)′ is, independently, H, A¹, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.

In some embodiments, each of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, andR^(G5)′ is, independently, H, A¹, F, Cl,

In some embodiments, each of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, andR^(G5)′ is, independently, H, A¹, F,

In some embodiments, each of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, andR^(G5)′ is, independently, H, A¹, F, Cl,

In some embodiments, R^(G3)′ is A¹.

In some embodiments, R^(G1)′ is H; R^(G2)′ is

R^(G3)′ is A¹; R^(G4)′ is

and R^(G5)′ is H. In some embodiments, R^(G1)′ is H; R^(G2)′ is

R^(G3)′ is A; R^(G4)′ is H; and R^(G5)′ is

In some embodiments, R^(G1)′ is H; R^(G2)′ is

R^(G3)′ is A¹; R^(G4)′ is Cl or F; and R^(G5)′ is H. In someembodiments, R^(G1)′ is H; R^(G2)′ is

R^(G3)′ is A¹; R^(G4)′ is H; and R^(G5)′ is H. In some embodiments,R^(G1)′ is H; R^(G2)′ is

R^(G3)′ is A¹; R^(G4)′ is

and R^(G5)′ is H.

In some embodiments, R^(G1)′ and R^(G2)′, R^(G2)′ and R^(G3)′, R^(G3)′and R^(G4), and/or R^(G4)′ and R^(G5)′, together with the carbon atomsto which each is attached, combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A¹, where one of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′ andR^(G5)′ is A¹, or

is substituted with A¹. In some embodiments, R^(G1)′ and R^(G2)′,R^(G2)′ and R^(G3)′, R^(G3)′, and R^(G4)′, and/or R^(G4)′ and R^(G5)′,together with the carbon atoms to which each is attached, combine toform

; and

is optionally substituted C₂-C₉ heteroaryl, which is optionallysubstituted with A¹, where one of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′,and R^(G5)′ is A¹, or

is substituted with A¹.

In some embodiments, G′ is

where R^(G6)′ is H, A¹, or optionally substituted C₁-C₆ alkyl. In someembodiments, G′ is

where R^(G6)′ is H, A¹, or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(G1)′ and R^(G2)′, R^(G2)′ and R^(G3)′, R^(G3)′and R^(G4)′, and/or R^(G4)′ and R^(G5)′, together with the carbon atomsto which each is attached, combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl or optionally substitutedC₂-C₉ heteroaryl, any of which is optionally substituted with A¹, whereone of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, and R^(G5)′ is A¹, or

is substituted with A¹.

In some embodiments, G′ is

where R^(G6)′ is H, A¹, or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(G6)′ is H, A¹,

In some embodiments, R^(G6)′ is H, A¹, or

In some embodiments, R^(G6)′ is H or A¹.

In some embodiments, R^(G6)′ is H. In some embodiments, R^(G6)′ is A¹.

In some embodiments, R^(G1)′ is H, A¹, F,

In some embodiments, R^(G1)′ is H.

In some embodiments, R^(G2)′ is H, A¹, F,

In some embodiments, R^(G2)′ is H.

In some embodiments, R^(G3)′ is H, A¹, F,

In some embodiments, R^(G3)′ is H.

In some embodiments, R^(G4)′ is H, A¹, F,

In some embodiments, R^(G4)′ is H.

In some embodiments, R^(G5)′ is H, A¹, F,

In some embodiments, R^(G5)′ is H.

In some embodiments, one or more of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′,and R^(G5)′ is H. In some embodiments, two or more of R^(G1)′, R^(G2)′,R^(G3)′, R^(G4)′, and R^(G5)′ is H. In some embodiments, three or moreof R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, and R^(G5)′ is H.

In some embodiments, R^(G1)′ is A¹. In some embodiments, R^(G2)′ is A¹.In some embodiments, R^(G3)′ is A¹. In some embodiments, R^(G4)′ is A¹.In some embodiments, R^(G5)′ is A¹. In some embodiments,

is substituted with A¹.

In some embodiments, G′ is

where

each of R^(G7)′, R^(G8)′, R^(G9)′, R^(G10)′, and R^(G11)′ is,independently, H, A¹, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G7)′ and R^(G8)′, R^(G8)′ and R^(G9)′, R^(G9)′and R^(G10)′, and/or R^(G10)′ and R^(G11)′, together with the carbonatoms to which each is attached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A¹, where oneof R^(G7)′, R^(G8)′, R^(G9)′, R^(G10)′, and R^(G11)′ is A¹; or

is substituted with A¹.

In some embodiments, each of R^(G7)′, R^(G8)′, R^(G9)′, R^(G10)′, andR^(G11)′ is, independently, H, A¹, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl,optionally substituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, oroptionally substituted amino; or R^(G7)′ and R^(G8)′, R^(G8)′ andR^(G9)′, R^(G9)′ and R^(G10)′, and/or R^(G10)′ and R^(G11)′, togetherwith the carbon atoms to which each is attached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A¹, where oneof R^(G7)′, R^(G8)′, R^(G9)′, R^(G10)′, and R^(G11)′ is A¹; or

is substituted with A¹.

In some embodiments, each of R^(G7)′, R^(G8)′, R^(G9)′, R^(G10)′, andR^(G11)′ is, independently, H, A¹, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl; or R^(G7)′ and R^(G8)′, R^(G8)′ and R^(G9)′, R^(G9)′ andR^(G10)′, and/or R^(G10)′ and R^(G11)′, together with the carbon atomsto which each is attached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A¹, where oneof R^(G7)′, R^(G8)′, R^(G9)′, R^(G10)′, and R^(G11)′ is A¹; or

is substituted with A¹.

In some embodiments, each of R^(G7)′, R^(G8)′, R^(G9)′, R^(G10)′, andR^(G11)′ is, independently, H, A¹, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.

In some embodiments, each of R^(G7)′, R^(G8)′, R^(G9)′, R^(G10)′, andR^(G11)′ is, independently, H, A¹, F, Cl,

In some embodiments, R^(G8)′ is

In some embodiments, G′ is

In some embodiments, R^(G7)′ is H; R^(G8)′ is

R^(G9)′ is A1; and R^(G11)′ is H.

In some embodiments, G′ is

where

each of R^(G12)′, R^(G13)′, and R^(G14)′ is, independently, H, A¹,halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G12)′ and R^(G14)′ together with the carbon atoms to which each isattached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or optionallysubstituted C₂-C₉ heterocyclyl, any of which is optionally substitutedwith A¹, where one of R^(G12)′, R^(G13)′, and R^(G14)′ is A¹; or

is substituted with A¹.

In some embodiments, each of R^(G12)′, R^(G13)′, and R^(G14)′ is,independently, H, A¹, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G12)′ and R^(G14)′, together with the carbonatoms to which each is attached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or optionallysubstituted C₂-C₉ heterocyclyl, any of which is optionally substitutedwith A¹, where one of R^(G12)′, R^(G13)′, and R^(G14)′ is A¹; or

is substituted with A¹.

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₁-C₆ acyl,optionally substituted sulfone, or optionally substituted sulfonamide.In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted sulfone, oroptionally substituted sulfonamide. In some embodiments, each of R^(3a)′R^(3b)′, R^(3c)′, and R^(3d)′ is, independently, H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ acyl, optionallysubstituted sulfone, or optionally substituted sulfonamide. In someembodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ acyl.

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₁-C₆ acyl,optionally substituted sulfone, or optionally substituted sulfonamide.In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c), and R^(3d)′ is,independently, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ acyl, optionally substituted sulfone, or optionallysubstituted sulfonamide. In some embodiments, each of R^(3a)′, R^(3b)′,R^(3c)′, and R^(3d)′ is, independently, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₁-C₆ acyl. In some embodiments, each of R^(3a)′, R^(3b)′,R^(3c)′, and R^(3d)′ is, independently, optionally substituted C₁-C₆alkyl or optionally substituted C₁-C₆ heteroalkyl. In some embodiments,each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is, independently,optionally substituted C₁-C₆ alkyl or optionally substituted C₁-C₆ acyl.In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, or optionally substituted C₁-C₆ acyl. In someembodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, optionally substituted sulfone, or optionally substitutedsulfonamide.

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H, optionally substituted C₁-C₆ alkyl,

where

R⁶ is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, oroptionally substituted C₆-C₁₀ aryl;

W¹ is O or S;

W² is NR⁷ or O;

R⁷ is H, optionally substituted C₁-C₆ alkyl, or optionally substitutedC₁-C₆ heteroalkyl;

R⁸ is optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, or optionallysubstituted C₆-C₁₀ aryl; and

R⁹ is H, optionally substituted C₁-C₆ alkyl, or optionally substitutedC₁-C₆ heteroalkyl.

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, C₁-C₆ alkyl,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, or C₁-C₆ alkyl. In some embodiments, each of R^(3a)′,R^(3b)′, R^(3c)′, and R^(3d)′ is, independently,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H, optionally substituted C₁-C₆ alkyl,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c), and R^(3d)′ is,independently, H, C₁-C₆ alkyl,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H, C₁-C₆ alkyl, or

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, C₁-C₆ alkyl or

In some embodiments, each of R^(3a), R^(3b), R^(3c), and R^(3d) is,independently, H, methyl, or

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, optionally substituted C₁-C₆ alkyl.

In some embodiments, W¹ is O. In some embodiments, W¹ is S.

In some embodiments, W² is O. In some embodiments, W² is NR⁷.

In some embodiments, R⁶ is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, or optionally substitutedC₃-C₁₀ carbocyclyl. In some embodiments, R⁶ is H, optionally substitutedC₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl. In someembodiments, R⁶ is H, optionally substituted C₃-C₁₀ carbocyclyl, oroptionally substituted C₆-C₁₀ aryl. In some embodiments, R⁶ isoptionally substituted C₁-C₆ alkyl or optionally substituted C₁-C₆heteroalkyl. In some embodiments, R⁶ is optionally substituted C₃-C₁₀carbocyclyl or optionally substituted C₆-C₁₀ aryl

In some embodiments, R⁶ is H, methyl, ethyl,

In some embodiments, R⁶ is H or

In some embodiments, R⁶ is methyl, ethyl,

In some embodiments, R⁶ is or

In some embodiments, R⁶ is H. In some embodiments, R⁶ is H, methyl,ethyl,

In some embodiments, R⁷ is H or optionally substituted C₁-C₆ alkyl. Insome embodiments, R⁷ is H or methyl.

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c), and R^(3d)′ is,independently, H, methyl,

In some embodiments, each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H, methyl,

In some embodiments, R^(3a)′ is H, methyl,

In some embodiments, R^(3b)′ is H, methyl,

In some embodiments, R^(3c)′ is H, methyl,

In some embodiments, R^(3d)′ is H, methyl,

In some embodiments, A has the structure of Formula IIIa:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIb:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIc:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIId:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIe:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIf:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIg:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIh:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIi:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIj:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIk:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIm:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIn:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIo:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIp:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIq:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIr:

or a pharmaceutically acceptable salt thereof.

In some embodiments, A has the structure of Formula IIIs:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the degradation moiety is a ubiquitin ligasebinding moiety.

In some embodiments, the ubiquitin ligase binding moiety comprisesCereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse doubleminute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands, orderivatives or analogs thereof.

In some embodiments, the degradation moiety is a ubiquitin ligasebinding moiety.

In some embodiments, the ubiquitin ligase binding moiety comprisesCereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse doubleminute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands, orderivatives or analogs thereof.

In some embodiments, the degradation moiety includes the structure ofFormula Y:

where

A² is a bond between the degradation moiety and the linker;

v1 is 0, 1, 2, 3, 4, or 5;

u1 is 1, 2, or 3;

T¹ is a bond or

T² is

R^(5A) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl;

each R^(J1) is, independently, halogen, optionally substituted C₁-C₆alkyl, or optionally substituted C₁-C₆ heteroalkyl; and

J is absent, optionally substituted C₃-C₁₀ carbocyclylene, optionallysubstituted C₆-C₁₀ arylene, optionally substituted C₂-C₉heterocyclylene, or optionally substituted C₂-C₉ heteroarylene, or apharmaceutically acceptable salt thereof.

In some embodiments, T¹ is a bond. In some embodiments, T¹ is

In some embodiments, T² is

In some embodiments, T² is or

In some embodiments, T² is

In some embodiments, the structure of Formula Y has the structure ofFormula Y1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula Y has the structure ofFormula Y2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula Y has the structure ofFormula Z:

or a pharmaceutically acceptable salt thereof.

In some embodiments, u1 is 1. In some embodiments, u1 is 2. In someembodiments u1 is 3.

In some embodiments, the structure of Formula Z has the structure ofFormula AA:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula Z has the structure ofFormula AB:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula Z has the structure ofFormula AC:

or a pharmaceutically acceptable salt thereof.

In some embodiments, v1 is 0, 1, 2, or 3. In some embodiments, v1 is 0.In some embodiments, v1 is 1. In some embodiments, v1 is 2. In someembodiments, v1 is 3.

In some embodiments, the structure of Formula AA has the structure ofFormula AA1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula AB has the structure ofFormula AB1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula AC has the structure ofFormula AC1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, J is absent. In some embodiments, J is optionallysubstituted C₃-C₁₀ carbocyclylene or optionally substituted C₆-C₁₀arylene. In some embodiments, J is optionally substituted C₂-C₉heterocyclylene or optionally substituted C₂-C₉ heteroarylene.

In some embodiments, J is optionally substituted heterocyclylene. Insome embodiments, J is optionally substituted C₆-C₁₀ arylene.

In some embodiments, the structure of Formula AA has the structure ofFormula AA2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula AA has the structure ofFormula AA3:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula AA has the structure ofFormula AA4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, R^(A)S is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(A5) is H or methyl. In some embodiments, R^(A5)is H. In some embodiments, R^(A5) is methyl.

In some embodiments, the structure of Formula AA has the structure ofFormula A:

where

Y¹ is

R^(A5) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl;

R^(A6) is H or optionally substituted C₁-C₆ alkyl; and R^(A7) is H oroptionally substituted C₁-C₆ alkyl; or R^(A6) and R^(A7), together withthe carbon atom to which each is bound, combine to form optionallysubstituted C₃-C₆ carbocyclyl or optionally substituted C₂-C₅heterocyclyl; or R^(A6) and R^(A7), together with the carbon atom towhich each is bound, combine to form optionally substituted C₃-C₆carbocyclyl or optionally substituted C₂-C₅ heterocyclyl;

R^(A8) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl;

each of R^(A1), R^(A2), R^(A3), and R^(A4) is, independently, H, A²,halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(A1) and R^(A2), R^(A2) and R^(A3), and/orR^(A3) and R^(A4), together with the carbon atoms to which each isattached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A², where oneof R^(A1), R^(A2), R^(A3), and R^(A4) is A², or

is substituted with A², or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R^(A1), R^(A2), R^(A3), and R^(A4) is,independently, H, A², halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; orR^(A1) and R^(A2), R^(A2) and R^(A3), and/or R^(A3) and R^(A4), togetherwith the carbon atoms to which each is attached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A², where oneof R^(A1), R^(A2), R^(A3), and R^(A4) is A², or

is substituted with A², or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R^(A1), R^(A2), R^(A3), and R^(A4) is, H,A², halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted —O—C₃-C₆ carbocyclyl,hydroxyl, optionally substituted amino; or R^(A1) and R^(A2), R^(A2) andR^(A3), or R^(A3) and R^(A4), together with the carbon atoms to whicheach is attached, combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², where one of R^(A1), R^(A2), R^(A3), and R^(A4) isA², or

is substituted with A².

In some embodiments, each of R^(A1), R^(A2), R^(A3), and R^(A4) is,independently, H, A², F,

or R^(A1) and R^(A)2, R^(A)2 and R^(A3), or R^(A3) and R^(A4), togetherwith the carbon atoms to which each is attached, combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², where one of R^(A1), R^(A2), R^(A3), and R^(A4) isA², or

is substituted with A².

In some embodiments, R^(A1) is A². In some embodiments, R^(A2) is A². Insome embodiments, R^(A3) is A². In some embodiments, R^(A4) is A². Insome embodiments, R^(A5) is A².

In some embodiments, R^(A5) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(A5) is H or

In some embodiments, R^(A5) is H. In some embodiments, R^(A5) is

In some embodiments, Y¹ is

In some embodiments, Y¹ is

In some embodiments, Y¹ is

In some embodiments, each of R^(A6) and R^(A7) is, independently, H, F,

or R^(A6) and R^(A7), together with the carbon atom to which each isbound, combine to form

In some embodiments, Y¹ is

In some embodiments, the structure of Formula A has the structure ofFormula A1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A3:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A5:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A6:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A7:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A8:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A9:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula A has the structure ofFormula A10:

or a pharmaceutically acceptable salt thereof.

In some embodiments, wherein the structure of Formula A is

or derivative or analog thereof.

In some embodiments, the structure of Formula A is

In some embodiments, the structure of Formula A is

or derivative or analog thereof.

In some embodiments,

where R^(A9) is H, A², optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl.

In some embodiments, the structure of Formula A is

In some embodiments, R^(A9) is H, A², or optionally substituted C₁-C₆alkyl. In some embodiments, R^(A9) is H, A², or methyl. In someembodiments, R^(9A) is H. In some embodiments, R^(9A) is methyl. In someembodiments, R^(A9) is A².

In some embodiments, the structure of Formula A is

In some embodiments, the structure of Formula AA has the structure ofFormula B:

where

R^(A5) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl;

each of R^(A1), R^(A2), R^(A3), and R^(A4) is, independently, H, A²,halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(A1) and R^(A2), R^(A2) and R^(A3), and/orR^(A3) and R^(A4), together with the carbon atoms to which each isattached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A², where oneof R^(A1), R^(A2), R^(A3), and R^(A4) is A², or

is substituted with A², or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R^(A1), R^(A2), R^(A3), and R^(A4) is, H,A², halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted —O—C₃-C₆ carbocyclyl,hydroxyl, optionally substituted amino; or R^(A1) and R^(A2), R^(A2) andR^(A3), or R^(A3) and R^(A4), together with the carbon atoms to whicheach is attached, combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², where one of R^(A1), R^(A2), R^(A3), and R^(A4) isA², or

is substituted with A².

In some embodiments, each of R^(A1), R^(A2), R^(A3), and R^(A4) is,independently, H, A², F,

or R^(A1) and R^(A2), R^(A2) and R^(A3), or R^(A3) and R^(A4), togetherwith the carbon atoms to which each is attached, combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², where one of R^(A1), R^(A2), R^(A3), and R^(A4) isA², or

is substituted with A².

In some embodiments, R^(A1) is A². In some embodiments, R^(A2) is A². Insome embodiments, R^(A3) is A². In some embodiments, R^(A4) is A². Insome embodiments, R^(A5) is A².

In some embodiments, R^(A5) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(A5) is H or

In some embodiments, R^(A5) is H. In some embodiments, R^(A5) is

In some embodiments, the structure of Formula B has the structure ofFormula B1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula B has the structure ofFormula B2:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula B has the structure ofFormula B3:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula B has the structure ofFormula B4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula B is

In some embodiments, the structure of Formula B is

In some embodiments, the structure of Formula B is

In some embodiments, the ubiquitin ligase binding moiety comprises a vonHippel-Lindau ligand.

In some embodiments, the von Hippel-Lindau ligand has the structure of

or derivative or analog thereof.

In some embodiments, the degradation moiety includes the structure ofFormula C:

where

R^(B1) is H, A², optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl;

R^(B2) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl;

R^(B3) is A², optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₁-C₆ alkyl C₃-C₁₀carbocyclyl, or optionally substituted C₁-C₆ alkyl C₆-C₁₀ aryl;

R^(B4) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or optionally substitutedC₁-C₆ alkyl C₆-C₁₀ aryl;

R^(B5) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl;

v2 is 0, 1, 2, 3, or 4;

each R^(B6) is, independently, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino;and

each of R^(B7) and R^(B8) is, independently, H, halogen, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₆-C₁₀ aryl,

where one of R^(B1) and R^(B3) is A², or a pharmaceutically acceptablesalt thereof.

In some embodiments, the structure of Formula C is

or derivative or analog thereof.

In some embodiments, the structure of Formula C is

In some embodiments, the degrader moiety includes the structure ofFormula D:

where

A² is a bond between B and the linker;

each of R^(C1), R^(C2), and R^(C7) is, independently, H, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl;

R^(C3) is optionally substituted C₁-C₆ alkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or optionally substitutedC₁-C₆ alkyl C₆-C₁₀ aryl;

R^(C5) is optionally substituted C₁-C₆ alkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or optionally substitutedC₁-C₆ alkyl C₆-C₁₀ aryl;

v3 is 0, 1, 2, 3, or 4;

each R^(C8) is, independently, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino;

v4 is 0, 1, 2, 3, or 4; and

each R^(C9) is, independently, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino, ora pharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula D is

or derivative or analog thereof.

In some embodiments, the degrader moiety includes the structure ofFormula E:

where

A² is a bond between B and the linker;

each of R^(C10) and R^(C11) is, independently, H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₁-C₆ alkyl C₃-C₁₀carbocyclyl, or optionally substituted C₁-C₆ alkyl C₆-C₁₀ aryl;

v5 is 0, 1, 2, 3, or 4;

each R^(C12) is, independently, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino;

v6 is 0, 1, 2, 3, or 4; and

each R²¹ is, independently, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxy, thiol, or optionally substituted amino, or apharmaceutically acceptable salt thereof.

In some embodiments, the structure of Formula E is

or derivative or analog thereof.

In some embodiments, the degradation moiety includes the structure ofFormula FA:

where

or a bicyclic moiety which is substituted with A² and substituted withone or more groups independently selected from H, R^(FF1), and oxo;

is a single bond or a double bond;

u2 is 0, 1, 2, or 3;

A² is a bond between the degrader and the linker;

Y^(Fa) is CR^(Fb)R^(Fc), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

Y^(Fb) is NH, NR^(FF1), CH₂, CHR^(FF1), C(R^(FF1))₂, O, or S;

Y^(Fc) is CR^(Fd)R^(Fe), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

each of R^(Fb), R^(Fc), R^(Fd), and R^(Fe) is, independently, H, alkyl,aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxyl,alkoxy, amino, —NHalkyl, or —Nalkyl₂;

or R^(Fb) and R^(Fc), together with the carbon atom to which each isattached, combine to form a 3-, 4-, 5-, or 6-memberedspirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylenecomprising 1 or 2 heteroatoms selected from N and O;

or R^(Fd) and R^(Fe), together with the carbon atom to which each isattached, combine to form a 3-, 4-, 5-, or 6-memberedspirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylenecomprising 1 or 2 heteroatoms selected from N and O; and

or R^(Fd) and R^(Fb), together with the carbon atoms to which each isattached, combine to form a 1, 2, 3, or 4 carbon bridged ring;

each of Y^(Fd) and Y^(Ff) is, independently, CH₂, CHR^(FF2),C(R^(FF2))₂, C(O), N, NH, NR^(FF3), O, S, or S(O);

Y^(Fe) is a bond or a divalent moiety attached to Y^(Fd) and Y^(Ff) thatcontains 1 to 5 contiguous carbon atoms that form a 3 to 8-memberedring,

-   -   wherein 1, 2, or 3 carbon atoms can be replaced with a nitrogen,        oxygen, or sulfur atom;    -   wherein one of the ring atoms is substituted with A² and the        others are substituted with one or more groups independently        selected from H and R^(FF1); and    -   wherein the contiguous atoms of Y^(Fe) can be attached through a        single or double bond;

each R^(FF1) is, independently, H, alkyl, alkenyl, alkynyl, aliphatic,heteroaliphatic, carbocyclyl, halogen, hydroxyl, amino, cyano, alkoxy,aryl, heteroaryl, heterocyclyl, alkylamino, alkylhydroxyl, or haloalkyl;

each R^(FF2) is, independently, alkyl, alkene, alkyne, halogen,hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)(aliphatic,including alkyl), —C(O)O(aliphatic, including alkyl), —NH(aliphatic,including alkyl), —N(aliphatic including alkyl)(aliphatic includingalkyl), —NHSO₂alkyl, —N(alkyl)SO₂alkyl, —NHSO₂aryl, —N(alkyl)SO₂aryl,—NHSO₂alkenyl, —N(alkyl)SO₂alkenyl, —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl,aliphatic, heteroaliphatic, aryl, heteroaryl, hetercyclic, carbocyclic,cyano, nitro, nitroso, —SH, —Salkyl, or haloalkyl; and

R^(FF3) is alkyl, alkenyl, alkynyl, —C(O)H, —C(O)OH, —C(O)alkyl, or—C(O)Oalkyl,

wherein if Y^(Fd) or Y^(Ff) is substituted with A², then Y^(Fe) is abond, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula FA has the structure ofFormula FA1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the degradation moiety includes the structure ofFormula FB:

where

or a bicyclic moiety which is substituted with A² and substituted withone or more groups independently selected from H, R^(FF1), and oxo;

A² is a bond between the degrader and the linker;

Y^(Fa) is CR^(Fb)R^(Fc), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

each of Y^(Fb) and Y^(Fg) is, independently, NH, NR^(FF1), CH₂,CHR^(FF1), C(RFF¹)₂, O, or S;

Y^(Fc) is CR^(Fd)R^(Fe), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;

each of R^(Fb), R^(Fc), R^(Fd), R^(Fe), R^(Ff), and R^(Fg) is,independently, H, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl,carbocyclyl, hydroxyl, alkoxy, amino, —NHalkyl, or —Nalkyl₂;

or R^(Fb) and R^(Fc), together with the carbon atom to which each isattached, combine to form a 3-, 4-, 5-, or 6-memberedspirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylenecomprising 1 or 2 heteroatoms selected from N and O;

or R^(Fd) and R^(Fe), together with the carbon atom to which each isattached, combine to form a 3-, 4-, 5-, or 6-memberedspirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylenecomprising 1 or 2 heteroatoms selected from N and O;

or R^(Ff) and R^(Fg), together with the carbon atom to which each isattached, combine to form a 3-, 4-, 5-, or 6-memberedspirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylenecomprising 1 or 2 heteroatoms selected from N and O;

or R^(Fd) and R^(Fb), together with the carbon atoms to which each isattached, combine to form a 1, 2, 3, or 4 carbon bridged ring;

or R^(Fd) and R^(Ff), together with the carbon atoms to which each isattached, combine to form a 1, 2, 3, or 4 carbon bridged ring;

or R^(F)b and R^(Fg), together with the carbon atoms to which each isattached, combine to form a 1, 2, 3, or 4 carbon bridged ring;

each of Y^(Fd) and Y^(Ff) is, independently, CH₂, CHR^(FF2),C(R^(FF2))₂, C(O), N, NH, NR^(FF3), O, S, or S(O);

Y^(Fe) is a bond or a divalent moiety attached to Y^(Fd) and Y^(Ff) thatcontains 1 to 5 contiguous carbon atoms that form a 3 to 3-memberedring,

-   -   wherein 1, 2, or 3 carbon atoms can be replaced with a nitrogen,        oxygen, or sulfur atom;    -   wherein one of the ring atoms is substituted with A² and the        others are substituted with one or more groups independently        selected from H and R^(FF1); and    -   wherein the contiguous atoms of Y^(Fe) can be attached through a        single or double bond;

each R^(FF1) is, independently, H, alkyl, alkenyl, alkynyl, aliphatic,heteroaliphatic, carbocyclyl, halogen, hydroxyl, amino, cyano, alkoxy,aryl, heteroaryl, heterocyclyl, alkylamino, alkylhydroxyl, or haloalkyl;

each R^(FF2) is, independently, alkyl, alkene, alkyne, halogen,hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)(aliphatic,including alkyl), —C(O)O(aliphatic, including alkyl), —NH(aliphatic,including alkyl), —N(aliphatic including alkyl)(aliphatic includingalkyl), —NHSO₂alkyl, —N(alkyl)SO₂alkyl, —NHSO₂aryl, —N(alkyl)SO₂aryl,—NHSO₂alkenyl, —N(alkyl)SO₂alkenyl, —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl,aliphatic, heteroaliphatic, aryl, heteroaryl, hetercyclic, carbocyclic,cyano, nitro, nitroso, —SH, —Salkyl, or haloalkyl; and

RFF³ is alkyl, alkenyl, alkynyl, —C(O)H, —C(O)OH, —C(O)alkyl, or—C(O)Oalkyl,

wherein if Y^(Fd) or is substituted with A², then Y^(Fe) is a bond, or apharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula FB has the structure ofFormula FB1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the degradation moiety includes the structure ofFormula F1:

where A² is a bond between the degrader and the linker; and R^(F1) isabsent or O, or a pharmaceutically acceptable salt thereof.

In some embodiments, R^(F1) is absent. In some embodiments, R^(F1) is O.

In some embodiments, the structure of Formula F1 is

In some embodiments, the degradation moiety includes the structureFormula F2:

where A² is a bond between the degrader and the linker; and Y² is CH₂ orNH, or a pharmaceutically acceptable salt thereof.

In some embodiments, Y² is NH. In some embodiments, Y² is CH₂.

In some embodiments, structure of Formula F2 is

In some embodiments, the degradation moiety includes the structureFormula G:

where A² is a bond between the degrader and the linker; and Y³ is CH₂ orNH, or a pharmaceutically acceptable salt thereof.

In some embodiments, Y³ is NH. In some embodiments, Y³ is CH₂.

In some embodiments, structure of Formula G is

The degradation moiety may also include structures found in, e.g.,WO2017/197036; WO2019/204354, WO2019/236483, WO2020/010177; andWO2020/010227, the structures of which are herein incorporated byreference.

In some embodiments, the linker has the structure of Formula IV:

A¹-(B¹)_(f)-(C¹)_(g)-(B²)_(h)-(D)-(B³)_(i)-(C²)_(j)-(B⁴)_(k)-A²  Formula IV

where

A¹ is a bond between the linker and A;

A² is a bond between B and the linker;

each of B¹, B², B³, and B⁴ is, independently, optionally substitutedC₁-C₂ alkylene, optionally substituted C₁-C₃ heteroalkylene, O, S,S(O)₂, or NR^(N);

each R^(N) is, independently, H, optionally substituted C₁₋₄ alkyl,optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄alkynyl, optionally substituted C₂₋₆ heterocyclyl, optionallysubstituted C₆₋₁₂ aryl, or optionally substituted C₁₋₇ heteroalkyl;

each of C¹ and C² is, independently, carbonyl, thiocarbonyl, sulphonyl,or phosphoryl;

each of f, g, h, i, j, and k is, independently, 0 or 1; and

D is optionally substituted C₁₋₁₀ alkylene, optionally substituted C₂₋₁₀alkenylene, optionally substituted C₂₋₁₀ alkynylene, optionallysubstituted C₂₋₆ heterocyclylene, optionally substituted C₆₋₁₂ arylene,optionally substituted C₂-C₁₀ polyethylene glycol, or optionallysubstituted C₁₋₁₀ heteroalkylene, or a chemical bond linkingA¹-(B¹)_(f)-(C¹)_(g)-(B²)_(h)- to -(B³)_(i)-(C²)_(j)-(B⁴)_(k)-A².

In some embodiments, each of B¹, B², B³, and B⁴ is, independently,optionally substituted C₁-C₄ alkylene, optionally substituted C₁-C₄heteroalkylene, or NR^(N).

In some embodiments, each R^(N) is, independently, H or optionallysubstituted C₁-C₄ alkylene.

In some embodiments, each R^(N) is, independently, H or methyl.

In some embodiments, each of B¹ and B⁴ is, independently,

In some embodiments, B¹ is

In some embodiments, each of C¹ and C² is, independently

In some embodiments, C¹ is

In some embodiments, B² is NR^(N). In some embodiments, B² is optionallysubstituted C₁-C₄ alkylene.

In some embodiments, f is 0. In some embodiments, f is 1. In someembodiments, g is 1. In some embodiments, h is 0. In some embodiments, his 1. In some embodiments, i is 0. In some embodiments, j is 0. In someembodiments, k is 0.

In some embodiments, the linker has the structure of

wherein

x is 1, 2, 3, 4, 5, 6, 7, or 8;

y is 1, 2, 3, or 4;

R^(x) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl;

R^(y) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl; and

W is O or NR^(w), wherein R^(w) is H, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₆ carbocyclyl.

In some embodiments, the linker has the structure of

In some embodiments, R^(x) is H or me optionally substituted C₁-C₆alkyl. In some embodiments, R^(y) is H or optionally substituted C₁-C₆alkyl. In some embodiments, R^(w) is H or optionally substituted C₁-C₆alkyl.

In some embodiments, R^(x) is H or methyl. In some embodiments, RY is Hor methyl. In some embodiments, R^(w) is H or methyl.

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of Formula V:

A¹-(E¹)-(F¹)—(C³)_(m)-(E³)_(n)-(F²)_(o1)-(F³)_(o2)-(E²)_(p)-A²,  Formula V

where

A¹ is a bond between the linker and A;

A² is a bond between B and the linker;

each of m, n, o1, o2, and p is, independently, 0 or 1;

each of E¹ and E² is, independently, O, S, NR^(N), optionallysubstituted C₁₋₁₀ alkylene, optionally substituted C₂₋₁₀ alkenylene,optionally substituted C₂₋₁₀ alkynylene, optionally substituted C₂-C₁₀polyethylene glycol, or optionally substituted C₁₋₁₀ heteroalkylene;

E³ is optionally substituted C₁-C₆ alkylene, optionally substitutedC₁-C₆ heteroalkylene, O, S, or NR^(N);

each R^(N) is, independently, H, optionally substituted C₁₋₄ alkyl,optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄alkynyl, optionally substituted C₂₋₆ heterocyclyl, optionallysubstituted C₆₋₁₂ aryl, or optionally substituted C₁₋₇ heteroalkyl;

C³ is carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; and

each of F¹, F², and F³ is, independently, optionally substituted C₃-C₁₀carbocyclylene, optionally substituted C₂₋₁₀ heterocyclylene, optionallysubstituted C₆-C₁₀ arylene, or optionally substituted C₂-C₉heteroarylene.

In some embodiments, the linker has the structure of Formula Va:

A¹-(E¹)-(F¹)—(C³)_(m)-(E²)_(p)-A².   Formula Va

In some embodiments, the linker has the structure of Formula Vb:

A¹-(E¹)-(F¹)-(E²)_(p)-A².   Formula Vb

In some embodiments, the linker has the structure of Formula Vc:

A¹-(E¹)-(F¹)-A².   Formula Vc

In some embodiments, the linker has the structure of Formula Vd:

A¹-(E¹)-(F¹)—(C³)_(m)-(F²)_(o1)-A².   Formula Vd

In some embodiments, the linker has the structure of Formula Ve:

A¹-(E¹)-(F¹)-(E³)_(n)-(F²)_(o1)-(E²)_(p)-A².   Formula Ve

In some embodiments, the linker has the structure of Formula Vf:

A¹-(E¹)-(F¹)-(C³)_(m)-(E³)n-(F²)_(o1)-(E²)_(p)-A².   Formula Vf

In some embodiments, the linker has the structure of Formula Vg:

A¹-(E¹)-(F¹)—(C³)_(m)-(E³)_(n)-(F²)_(o1)-(F³)_(o2)-(E²)_(p)-A²,  Formula Vg

In some embodiments, each of E¹ and E² is, independently, NR^(N),optionally substituted C₁₋₁₀ alkyl, optionally substituted C₂-C₁₀polyethylene glycol, or optionally substituted C₁₋₁₀ heteroalkyl.

In some embodiments, E³ is optionally substituted C₁-C₆ alkylene, O, S,or NR^(N);

In some embodiments, E³ is optionally substituted C₁-C₆ alkylene. Insome embodiments, E³ is optionally substituted C₁-C₃ alkylene. In someembodiments, E³ is O, S, or NR^(N).

In some embodiments, E³ is C₁-C₆ alkylene. In some embodiments, E³ isC₁-C₃ alkylene. In some embodiments, E³ is O.

In some embodiments, E³ is

where a is 0, 1, 2, 3, 4, or 5.

In some embodiments, E³ is

In some embodiments, each R^(N) is, independently, H or optionallysubstituted C₁₋₄ alkyl.

In some embodiments, each R^(N) is, independently, H or methyl.

In some embodiments, E¹ is

where a is 0, 1, 2, 3, 4, or 5.

In some embodiments, E¹ is

where a is 0, 1, 2, 3, 4, or 5.

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

where

b is 0, 1, 2, 3, 4, 5, or 6;

R^(a) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl;

R^(b) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl; and

R^(c) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl.

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, R^(a) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(b) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(c) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(a) is H or methyl. In some embodiments, R^(b) isH or methyl. In some embodiments, R^(c) is H or methyl.

In some embodiments, b is 0, 1, 2, or 3. In some embodiments, b is 0. Insome embodiments, b is 1. In some embodiments, b is 2. In someembodiments, b is 3.

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E¹ is

In some embodiments, E² is O, NR^(w),

wherein

c is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

d is 0, 1, 2, or 3;

e is 0, 1, 2, 3, 4, 5, or 6;

f is 0, 1, 2, 3, or 4;

R^(d) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl;

R^(e) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl;

R^(f) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl;

R^(g) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl; and

W is O or NR^(w), wherein R^(w) is H or optionally substituted C₁-C₆alkyl.

In some embodiments, E² is O, NR^(w),

In some embodiments, R^(d) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(e) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(f) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(g) is H or optionally substituted C₁-C₆ alkyl.In some embodiments, R^(w) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, R^(d) is H or methyl. In some embodiments, R^(e) isH or methyl. In some embodiments, R^(f) is H or methyl. In someembodiments, R^(g) is H or methyl. In some embodiments, R^(w) is H ormethyl.

In some embodiments, E² is

In some embodiments, E² is O,

In some embodiments, each of F¹, F², or F³ is, independently, optionallysubstituted C₃-C₁₀ carbocyclylene.

In some embodiments, the C₃-C₁₀ carbocyclylene is monocyclic. In someembodiments, the C₃-C₁₀ carbocyclylene is polycyclic.

In some embodiments, the C₃-C₁₀ carbocyclylene is bicyclic.

In some embodiments, the C₃-C₁₀ carbocyclylene is bridged. In someembodiments, the C₃-C₁₀ carbocyclylene is fused. In some embodiments,the C₃-C₁₀ carbocyclylene is spirocyclic.

In some embodiments, the C₃-C₁₀ carbocyclylene is

In some embodiments, F² is

In some embodiments, the C₃-C₁₀ carbocyclylene is

In some embodiments, F¹ is

In some embodiments, each of F¹, F², or F³ is, independently, optionallysubstituted C₂-C₉ heterocyclylene.

In some embodiments, the C₂-C₉ heterocyclylene is monocyclic. In someembodiments, the C₂-C₉ heterocyclylene is polycyclic.

In some embodiments, the C₂-C₉ heterocyclylene is bicyclic.

In some embodiments, the C₂-C₉ heterocyclylene is bridged. In someembodiments, the C₂-C₉ heterocyclylene is fused. In some embodiments,the C₂-C₉ heterocyclylene is spirocyclic.

In some embodiments, the C₂-C₉ heterocyclylene includes a quaternaryamine.

In some embodiments, the C₂-C₉ heterocyclylene is

where

q1 is 0, 1, 2, 3, or 4;

q2 is 0, 1, 2, 3, 4, 5, or 6;

q3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

each R^(h) is, independently, ²H, halogen, optionally substituted C₁-C₆alkyl, OR^(i2), or NR^(i3)R^(i4); or two R^(h) groups, together with thecarbon atom to which each is attached, combine to form optionallysubstituted C₃-C₁₀ carbocyclyl or optionally substituted C₂-C₉heterocyclyl; or two R^(h) groups, together with the carbon atoms towhich each is attached, combine to form optionally substituted C₃-C₁₀carbocyclyl or optionally substituted C₂-C₉ heterocyclyl;

R^(i1) is H or optionally substituted C₁-C₆ alkyl;

R^(i2) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl;

R^(i3) is H or optionally substituted C₁-C₆ alkyl; and

R^(i4) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, each R^(h) is, independently, halogen, optionallysubstituted C₁-C₆ alkyl, OR^(i2), or NR^(i3)R^(i4). In some embodiments,R^(i1) is H or optionally substituted C₁-C₆ alkyl. In some embodiments,R^(i2) is H or optionally substituted C₁-C₆ alkyl. In some embodiments,R^(i3) is H or optionally substituted C₁-C₆ alkyl. In some embodiments,R^(i4) is H or optionally substituted C₁-C₆ alkyl.

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, each R^(h) is, independently, halogen, optionallysubstituted C₁-C₆ alkyl, OR^(i2), or NR^(i3)R^(i4). In some embodiments,each R^(h) is, independently, halogen, optionally substituted C₁-C₆alkyl, or NR^(i3)R^(i4).

In some embodiments, each R^(h) is, independently, ²H, halogen, cyano,optionally substituted C₁-C₆ alkyl, OR^(i2), or NR^(i3)R^(i4). In someembodiments, two R^(h) groups, together with the carbon atom to whicheach is attached, combine to form optionally substituted C₃-C₁₀carbocyclyl or optionally substituted C₂-C₉ heterocyclyl. In someembodiments, two R^(h) groups, together with the carbon atoms to whicheach is attached, combine to form optionally substituted C₃-C₁₀carbocyclyl or optionally substituted C₂-C₉ heterocyclyl.

In some embodiments, each R^(h) is, independently, H, ²H, F, methyl,

In some embodiments, each R^(h) is, independently, F, methyl, orNR^(i3)R^(i4).

In some embodiments, q1 is 0, 1, or 2. In some embodiments, q1 is 0. Insome embodiments, q1 is 1. In some embodiments, q1 is 2.

In some embodiments, q2 is 0, 1, or 2. In some embodiments, q2 is 0. Insome embodiments, q2 is 1. In some embodiments, q2 is 2.

In some embodiments, q3 is 0, 1, or 2. In some embodiments, q3 is 0. Insome embodiments, q3 is 1. In some embodiments, q3 is 2.

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F² is

In some embodiments, F³ is

In some embodiments, R^(i1) is H or methyl. In some embodiments, R^(i2)is H or methyl. In some embodiments, R^(i3) is H or methyl. In someembodiments, R^(i4) is H or methyl.

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F² is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, the C₂-C₉ heterocyclylene is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F¹ is

In some embodiments, F² is

In some embodiments, F² is

In some embodiments, F² is

In some embodiments, each of F¹, F², or F³ is, independently, optionallysubstituted C₆-C₁₀ arylene.

In some embodiments, the C₆-C₁₀ arylene is

In some embodiments, each of F¹, F², or F³ is, independently, optionallysubstituted C₂-C₉ heteroarylene.

In some embodiments, the C₂-C₉ heteroarylene is

In some embodiments, F² is

In some embodiments, F² is

In some embodiments, C³ is

In some embodiments, C³ is

In some embodiments, m is 1. In some embodiments, p is 1.

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of:

In some embodiments, the linker is a bond.

In some embodiments, the linker is optionally substituted C₃-C₁₀carbocyclylene, optionally substituted C₂₋₁₀ heterocyclylene, optionallysubstituted C₆-C₁₀ arylene, or optionally substituted C₂-C₉heteroarylene.

In some embodiments, the linker is optionally substituted C₃-C₁₀carbocyclylene or optionally substituted C₂₋₁₀ heterocyclylene. In someembodiments, the linker is optionally substituted C₆-C₁₀ arylene oroptionally substituted C₂-C₉ heteroarylene.

In some embodiments, the linker is optionally substituted C₂₋₁₀heterocyclylene.

In some embodiments, the C₂-C₉ heterocyclylene is monocyclic. In someembodiments, the C₂-C₉ heterocyclylene is polycyclic.

In some embodiments, the C₂-C₉ heterocyclylene is bicyclic.

In some embodiments, the C₂-C₉ heterocyclylene is bridged. In someembodiments, the C₂-C₉ heterocyclylene is fused. In some embodiments,the C₂-C₉ heterocyclylene is spirocyclic.

In some embodiments, the linker has the structure of

In some embodiments, the linker has the structure of

In some embodiments, the compound has the structure of any one ofcompounds D1-D38 in Table 2A, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound has the structure of any oneof compounds D1-D33 in Table 2A, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound has the structure of any oneof compounds D34-D38 in Table 2A, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound has the structure of any oneof compounds D39-D302 in Table 2B, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound has the structure of any oneof compounds D303-D375 in Table 2C, or a pharmaceutically acceptablesalt thereof.

In some embodiments, the compound has the structure of any one ofcompounds D9, D22, D25, D28, or D29 in Table 2A, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the compound has thestructure of any one of compounds D39-D49, D51, D52, D55, D56, D58, D58,D63, D64, D68, D69, D71-D73, D76, D78, D80-89, D91, D93, D95-107, D109,D110, D112-119, D121, D123-D1256, D127, D128, D130-D136, D138-D143,D145-D147, D149, D151, D152, D154-D166, D169-D174, D178-D183, D195-D201,D222, D224, D227, D231, D246, D251, D253-256, D283, or D299-302 in Table2B, or a pharmaceutically acceptable salt thereof. In some embodiments,the compound has the structure of any one of compounds D303, D304,D306-D312, D314, D315, D317-D327, D329, D330, D332-336, D338-D342,D344-D348, D350, OR D353-D373, or a pharmaceutically acceptable saltthereof.

In an aspect, the disclosure features compounds D1-D38 in Table 2A, or apharmaceutically acceptable salt thereof.

In another aspect, the disclosure features compounds D1-D33 in Table 2A,or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure features compounds D39-D302 in Table2B, or a pharmaceutically acceptable salt thereof.

In yet another aspect, the disclosure features compounds D303-D375 inTable 2C, or a pharmaceutically acceptable salt thereof.

TABLE 2A Compounds D1-D38 of the Disclosure Compound No. Structure D1

D2

D3

D4

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

D15

D16

D17

D18

D19

D20

D21

D22

D23

D24

D25

D26

D27

D28

D29

D30

D31

D32

D33

D34

D35

D36

D37

D38

TABLE 2B Compounds D39-D302 of the Disclosure Com- pound No. StructureD39

D40

D41

D42

D43

D44

D45

D46

D47

D48

D49

D50

D51

D52

D53

D54

D55

D56

D57

D58

D59

D60

D61

D62

D63

D64

D65

D66

D67

D68

D69

D70

D71

D72

D73

D74

D75

D76

D77

D78

D79

D80

D81

D82

D83

D84

D85

D86

D87

D88

D89

D90

D91

D92

D93

D94

D95

D96

D97

D98

D99

D100

D101

D102

D103

D104

D105

D106

D107

D109

D110

D111

D112

D113

D114

D115

D116

D117

D118

D119

D120

D121

D122

D123

D124

D125

D126

D127

D128

D129

D130

D131

D132

D133

D134

D135

D136

D137

D138

D139

D140

D141

D142

D143

D144

D145

D146

D147

D148

D149

D150

D151

D152

D153

D154

D155

D156

D157

D158

D159

D161

D162

D163

D164

D165

D166

D167

D168

D169

D170

D171

D172

D173

D174

D175

D176

D177

D178

D179

D180

D181

D182

D183

D184

D185

D186

D187

D188

D189

D190

D191

D192

D193

D194

D195

D196

D197

D198

D199

D200

D201

D202

D203

D204

D205

D206

D207

D208

D209

D210

D211

D212

D213

D214

D215

D216

D217

D218

D219

D220

D221

D222

D223

D224

D225

D226

D227

D228

D229

D230

D231

D232

D233

D234

D235

D236

D237

D238

D239

D240

D241

D242

D243

D244

D245

D246

D247

D248

D249

D250

D251

D252

D253

D254

D255

D256

D257

D258

D259

D260

D261

D262

D263

D264

D265

D266

D267

D268

D269

D270

D271

D272

D273

D274

D275

D276

D277

D278

D279

D280

D281

D282

D283

D284

D285

D286

D287

D288

D289

D290

D291

D292

D293

D294

D295

D296

D297

D298

D299

D300

D301

D302

TABLE 2C Compounds D303-D375 of the Disclosure Compound No. Structure  D303

D304

D305

D306

D307

D308

D309

D310

D311

D312

D313

D314

D315

D316

D317

D318

D319

D320

D321

D322

D323

D324

D325

D326

D327

D328

D329

D330

D331

D332

D333

D334

D335

D336

D337

D338

D339

D340

D341

D342

D343

D344

D345

D346

D347

D348

D349

D350

D351

D352

D353

D354

D355

D356

D357

D358

D359

D360

D361

D362

D363

D364

D365

D366

D367

D368

D369

D370

D371

D372

D373

D374

D375

In an aspect, the disclosure features a compound having the structure ofDD1, or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure features a pharmaceutical compositionincluding any of the foregoing compounds, or pharmaceutically acceptablesalts thereof, and a pharmaceutically acceptable excipient.

In an aspect, the disclosure features a method of inhibiting the leveland/or activity of BRD9 in a cell, the method involving contacting thecell with an effective amount of any of the foregoing compounds, orpharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition thereof.

In another aspect, the disclosure features a method of reducing thelevel and/or activity of BRD9 in a cell, the method involving contactingthe cell with an effective amount of any of the foregoing compounds, orpharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition thereof.

In some embodiments, the cell is a cancer cell.

In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladdercancer, stomach cancer, pancreatic cancer, esophageal cancer, prostatecancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma(e.g., a soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-partsarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round celltumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinalstromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignantmesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma,low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamousor adenocarcinoma), stomach cancer, or breast cancer. In someembodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-celllymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer,stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer,renal cell carcinoma, melanoma, or colorectal cancer. In someembodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing'ssarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma),stomach cancer, or breast cancer. In some embodiments, the cancer issarcoma (e.g., synovial sarcoma or Ewing's sarcoma). In someembodiments, the sarcoma is synovial sarcoma.

In an aspect, the disclosure features a method of treating a BAFcomplex-related disorder in a subject in need thereof, the methodinvolving administering to the subject an effective amount of any of theforegoing compounds, or pharmaceutically acceptable salts thereof, or apharmaceutical composition thereof. In some embodiments, the BAFcomplex-related disorder is cancer. In some embodiments, the BAFcomplex-related disorder is infection.

In another aspect, the disclosure features a method of treating anSS18-SSX fusion protein-related disorder in a subject in need thereof,the method involving administering to the subject an effective amount ofany of the foregoing compounds, or pharmaceutically acceptable saltsthereof, or a pharmaceutical composition thereof. In some embodiments,the SS18-SSX fusion protein-related disorder is cancer. In someembodiments, the SS18-SSX fusion protein-related disorder is infection.In some embodiments of any of the foregoing methods, the SS18-SSX fusionprotein is a SS18-SSX1 fusion protein, a SS18-SSX2 fusion protein, or aSS18-SSX4 fusion protein.

In yet another aspect, the disclosure features a method of treating aBRD9-related disorder in a subject in need thereof, the method involvingadministering to the subject an effective amount of any of the foregoingcompounds, or pharmaceutically acceptable salts thereof, or apharmaceutical composition thereof. In some embodiments, theBRD9-related disorder is cancer. In some embodiments, the BRD9-relateddisorder is infection.

In some embodiments, the cancer is squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cellcarcinomas, cancer of the bladder, bowel, breast, cervix, colon,esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate,and stomach; leukemias; benign and malignant lymphomas, particularlyBurkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignantmelanomas; myeloproliferative diseases; sarcomas, including Ewing'ssarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas,peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using the disclosed compounds according to the present inventioninclude, for example, acute granulocytic leukemia, acute lymphocyticleukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma,adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer,anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma,Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer,bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stemglioma, breast cancer, triple (estrogen, progesterone and HER-2)negative breast cancer, double negative breast cancer (two of estrogen,progesterone and HER-2 are negative), single negative (one of estrogen,progesterone and HER-2 is negative), estrogen-receptor positive,HER2-negative breast cancer, estrogen receptor-negative breast cancer,estrogen receptor positive breast cancer, metastatic breast cancer,luminal A breast cancer, luminal B breast cancer, Her2-negative breastcancer, HER2-positive or negative breast cancer, progesteronereceptor-negative breast cancer, progesterone receptor-positive breastcancer, recurrent breast cancer, carcinoid tumors, cervical cancer,cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), colon cancer, colorectal cancer,craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuseastrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer,ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma,extrahepatic bile duct cancer, eye cancer, fallopian tube cancer,fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinalcancer, gastrointestinal carcinoid cancer, gastrointestinal stromaltumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma,hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkinlymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC),infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC),intestinal Cancer, intrahepatic bile duct cancer, invasive/infiltratingbreast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidneycancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases,leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma insitu, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma,male breast cancer, medullary carcinoma, medulloblastoma, melanoma,meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma,mesenchymous, mesothelioma metastatic breast cancer, metastatic melanomametastatic squamous neck cancer, mixed gliomas, monodermal teratoma,mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma,Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer,nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors(NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oatcell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oralcancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma,osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germcell tumor, ovarian primary peritoneal carcinoma, ovarian sex cordstromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma,paranasal sinus cancer, parathyroid cancer, pelvic cancer, penilecancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,pheochromocytoma, pilocytic astrocytoma, pineal region tumor,pineoblastoma, pituitary gland cancer, primary central nervous system(CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma,renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, softtissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, smallcell lung cancer (SCLC), small intestine cancer, spinal cancer, spinalcolumn cancer, spinal cord cancer, squamous cell carcinoma, stomachcancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throatcancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsilcancer, transitional cell cancer, tubal cancer, tubular carcinoma,undiagnosed cancer, ureteral cancer, urethral cancer, uterineadenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvarcancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-celllineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, AdultT-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma,Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL,Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia(JMML), acute promyelocytic leukemia (a subtype of AML), large granularlymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large Bcell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissuelymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large Bcell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenicmarginal zone lymphoma (SMZL); intravascular large B-cell lymphoma;primary effusion lymphoma; or lymphomatoid granulomatosis; B-cellprolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable,splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacyticlymphoma; heavy chain diseases, for example, Alpha heavy chain disease,Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma,solitary plasmacytoma of bone; extraosseous plasmacytoma; primarycutaneous follicle center lymphoma, T cell/histocyte rich large B-celllymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus(EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-celllymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma,plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associatedmulticentric, Castleman disease; B-cell lymphoma, unclassifiable, withfeatures intermediate between diffuse large B-cell lymphoma, or B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and classical Hodgkin lymphoma.

In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladdercancer, stomach cancer, pancreatic cancer, esophageal cancer, prostatecancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma(e.g., a soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-partsarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round celltumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinalstromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignantmesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma,low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamousor adenocarcinoma), stomach cancer, or breast cancer. In someembodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-celllymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer,stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer,renal cell carcinoma, melanoma, or colorectal cancer. In someembodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing'ssarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma),stomach cancer, or breast cancer. In some embodiments, the cancer issarcoma (e.g., synovial sarcoma or Ewing's sarcoma). In someembodiments, the sarcoma is synovial sarcoma.

In some embodiments, the infection is viral infection (e.g., aninfection with a virus of the Retroviridae family such as thelentiviruses (e.g. Human immunodeficiency virus (HIV) anddeltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human Tcell leukemia virus II (HTLV-II)); Hepadnaviridae family (e.g. hepatitisB virus (HBV)); Flaviviridae family (e.g. hepatitis C virus (HCV));Adenoviridae family (e.g. Human Adenovirus); Herpesviridae family (e.g.Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1(HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6),Herpesvitus K*, CMV, varicella-zoster virus); Papillomaviridae family(e.g. Human Papillomavirus (HPV, HPV E1)); Parvoviridae family (e.g.Parvovirus B19); Polyomaviridae family (e.g. JC virus and BK virus);Paramyxoviridae family (e.g. Measles virus); or Togaviridae family (e.g.Rubella virus)). In some embodiments, the disorder is Coffin Siris,Neurofibromatosis (e.g., NF-1, NF-2, or Schwannomatosis), or MultipleMeningioma. In an aspect, the disclosure features a method of treating acancer in a subject in need thereof, the method including administeringto the subject an effective amount of any of the foregoing compounds, orpharmaceutically acceptable salts thereof, or any of the foregoingpharmaceutical compositions.

In some embodiments, the cancer is squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cellcarcinomas, cancer of the bladder, bowel, breast, cervix, colon,esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate,and stomach; leukemias; benign and malignant lymphomas, particularlyBurkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignantmelanomas; myeloproliferative diseases; sarcomas, including Ewing'ssarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas,peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using the disclosed compounds according to the present inventioninclude, for example, acute granulocytic leukemia, acute lymphocyticleukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma,adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer,anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma,Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer,bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stemglioma, breast cancer, triple (estrogen, progesterone and HER-2)negative breast cancer, double negative breast cancer (two of estrogen,progesterone and HER-2 are negative), single negative (one of estrogen,progesterone and HER-2 is negative), estrogen-receptor positive,HER2-negative breast cancer, estrogen receptor-negative breast cancer,estrogen receptor positive breast cancer, metastatic breast cancer,luminal A breast cancer, luminal B breast cancer, Her2-negative breastcancer, HER2-positive or negative breast cancer, progesteronereceptor-negative breast cancer, progesterone receptor-positive breastcancer, recurrent breast cancer, carcinoid tumors, cervical cancer,cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), colon cancer, colorectal cancer,craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuseastrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer,ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma,extrahepatic bile duct cancer, eye cancer, fallopian tube cancer,fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinalcancer, gastrointestinal carcinoid cancer, gastrointestinal stromaltumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma,hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkinlymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC),infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC),intestinal Cancer, intrahepatic bile duct cancer, invasive/infiltratingbreast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidneycancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases,leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma insitu, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma,male breast cancer, medullary carcinoma, medulloblastoma, melanoma,meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma,mesenchymous, mesothelioma metastatic breast cancer, metastatic melanomametastatic squamous neck cancer, mixed gliomas, monodermal teratoma,mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma,Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer,nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors(NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oatcell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oralcancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma,osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germcell tumor, ovarian primary peritoneal carcinoma, ovarian sex cordstromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma,paranasal sinus cancer, parathyroid cancer, pelvic cancer, penilecancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer,pheochromocytoma, pilocytic astrocytoma, pineal region tumor,pineoblastoma, pituitary gland cancer, primary central nervous system(CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma,renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, softtissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, smallcell lung cancer (SCLC), small intestine cancer, spinal cancer, spinalcolumn cancer, spinal cord cancer, squamous cell carcinoma, stomachcancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throatcancer, thymoma/thymic carcinoma, thyroid cancer, tongue cancer, tonsilcancer, transitional cell cancer, tubal cancer, tubular carcinoma,undiagnosed cancer, ureteral cancer, urethral cancer, uterineadenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvarcancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-celllineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, AdultT-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma,Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL,Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia(JMML), acute promyelocytic leukemia (a subtype of AML), large granularlymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large Bcell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissuelymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large Bcell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenicmarginal zone lymphoma (SMZL); intravascular large B-cell lymphoma;primary effusion lymphoma; or lymphomatoid granulomatosis; B-cellprolymphocytic leukemia; splenic lymphoma/leukemia, unclassifiable,splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacyticlymphoma; heavy chain diseases, for example, Alpha heavy chain disease,Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma,solitary plasmacytoma of bone; extraosseous plasmacytoma; primarycutaneous follicle center lymphoma, T cell/histocyte rich large B-celllymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus(EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-celllymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma,plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associatedmulticentric, Castleman disease; B-cell lymphoma, unclassifiable, withfeatures intermediate between diffuse large B-cell lymphoma, or B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and classical Hodgkin lymphoma.

In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladdercancer, stomach cancer, pancreatic cancer, esophageal cancer, prostatecancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma(e.g., a soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-partsarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round celltumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinalstromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignantmesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma,low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamousor adenocarcinoma), stomach cancer, or breast cancer. In someembodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-celllymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer,stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer,renal cell carcinoma, melanoma, or colorectal cancer. In someembodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing'ssarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma),stomach cancer, or breast cancer. In some embodiments, the cancer issarcoma (e.g., synovial sarcoma or Ewing's sarcoma). In someembodiments, the sarcoma is synovial sarcoma.

In another aspect, the disclosure features a method for treating a viralinfection in a subject in need thereof. This method includesadministering to the subject an effective amount of any of the foregoingcompounds, or pharmaceutically acceptable salts thereof, or any of theforegoing pharmaceutical compositions. In some embodiments, the viralinfection is an infection with a virus of the Retroviridae family suchas the lentiviruses (e.g. Human immunodeficiency virus (HIV) anddeltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human Tcell leukemia virus II (HTLV-II)); Hepadnaviridae family (e.g. hepatitisB virus (HBV)), Flaviviridae family (e.g. hepatitis C virus (HCV)),Adenoviridae family (e.g. Human Adenovirus), Herpesviridae family (e.g.Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1(HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6),Herpesvitus K*, CMV, varicella-zoster virus), Papillomaviridae family(e.g. Human Papillomavirus (HPV, HPV E1)), Parvoviridae family (e.g.Parvovirus B19), Polyomaviridae family (e.g. JC virus and BK virus),Paramyxoviridae family (e.g. Measles virus), Togaviridae family (e.g.Rubella virus).

In another embodiment of any of the foregoing methods, the methodfurther includes administering to the subject an additional anticancertherapy (e.g., chemotherapeutic or cytotoxic agent or radiotherapy).

In particular embodiments, the additional anticancer therapy is: achemotherapeutic or cytotoxic agent (e.g., doxorubicin or ifosfamide), adifferentiation-inducing agent (e.g., retinoic acid, vitamin D,cytokines), a hormonal agent, an immunological agent, or ananti-angiogenic agent. Chemotherapeutic and cytotoxic agents include,but are not limited to, alkylating agents, cytotoxic antibiotics,antimetabolites, vinca alkaloids, etoposides, and others (e.g.,paclitaxel, taxol, docetaxel, taxotere, cis-platinum). A list ofadditional compounds having anticancer activity can be found in L.Brunton, B. Chabner and B. Knollman (eds). Goodman and Gilman's ThePharmacological Basis of Therapeutics, Twelfth Edition, 2011, McGrawHill Companies, New York, N.Y.

In particular embodiments, the compound of the invention and theadditional anticancer therapy and any of the foregoing compounds orpharmaceutical compositions are administered within 28 days of eachother (e.g., within 21, 14, 10, 7, 5, 4, 3, 2, or 1 days) or within 24hours (e.g., 12, 6, 3, 2, or 1 hours; or concomitantly) each in anamount that together are effective to treat the subject.

Chemical Terms

The terminology employed herein is for the purpose of describingparticular embodiments and is not intended to be limiting.

For any of the following chemical definitions, a number following anatomic symbol indicates that total number of atoms of that element thatare present in a particular chemical moiety. As will be understood,other atoms, such as hydrogen atoms, or substituent groups, as describedherein, may be present, as necessary, to satisfy the valences of theatoms. For example, an unsubstituted C₂ alkyl group has the formula—CH₂CH₃. When used with the groups defined herein, a reference to thenumber of carbon atoms includes the divalent carbon in acetal and ketalgroups but does not include the carbonyl carbon in acyl, ester,carbonate, or carbamate groups. A reference to the number of oxygen,nitrogen, or sulfur atoms in a heteroaryl group only includes thoseatoms that form a part of a heterocyclic ring.

Herein a phrase of the form “optionally substituted X” (e.g., optionallysubstituted alkyl) is intended to be equivalent to “X, wherein X isoptionally substituted” (e.g., “alkyl, wherein said alkyl is optionallysubstituted”). It is not intended to mean that the feature “X” (e.g.,alkyl) per se is optional. As described herein, certain compounds ofinterest may contain one or more “optionally substituted” moieties. Ingeneral, the term “substituted”, whether preceded by the term“optionally” or not, means that one or more hydrogens of the designatedmoiety are replaced with a suitable substituent, e.g., any of thesubstituents or groups described herein. Unless otherwise indicated, an“optionally substituted” group may have a suitable substituent at eachsubstitutable position of the group, and when more than one position inany given structure may be substituted with more than one substituentselected from a specified group, the substituent may be either the sameor different at every position. Combinations of substituents envisionedby the present disclosure are preferably those that result in theformation of stable or chemically feasible compounds. The term “stable”,as used herein, refers to compounds that are not substantially alteredwhen subjected to conditions to allow for their production, detection,and, in certain embodiments, their recovery, purification, and use forone or more of the purposes disclosed herein.

The term “aliphatic,” as used herein, refers to a saturated orunsaturated, straight, branched, or cyclic hydrocarbon. “Aliphatic” isintended herein to include, but is not limited to, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thusincorporates each of these definitions. In one embodiment, “aliphatic”is used to indicate those aliphatic groups having 1-20 carbon atoms. Thealiphatic chain can be, for example, mono-unsaturated, di-unsaturated,tri-unsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphaticgroups can be in a cis or trans configuration. In one embodiment, thealiphatic group contains from 1 to about 12 carbon atoms, more generallyfrom 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In oneembodiment, the aliphatic group contains from 1 to about 8 carbon atoms.In certain embodiments, the aliphatic group is C₁-C₂, C₁-C₃, C₁-C₄,C₁-C₅, or C₁-C₆. The specified ranges as used herein indicate analiphatic group having each member of the range described as anindependent species. For example, the term C₁-C₆ aliphatic as usedherein indicates a straight or branched alkyl, alkenyl, or alkynyl grouphaving from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to meanthat each of these is described as an independent species. For example,the term C₁-C₄ aliphatic as used herein indicates a straight or branchedalkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atomsand is intended to mean that each of these is described as anindependent species. In one embodiment, the aliphatic group issubstituted with one or more functional groups that results in theformation of a stable moiety.

The term “heteroaliphatic,” as used herein, refers to an aliphaticmoiety that contains at least one heteroatom in the chain, for example,an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate,nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom.In one embodiment, the only heteroatom is nitrogen. In one embodiment,the only heteroatom is oxygen. In one embodiment, the only heteroatom issulfur. “Heteroaliphatic” is intended herein to include, but is notlimited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment,“heteroaliphatic” is used to indicate a heteroaliphatic group (cyclic,acyclic, substituted, unsubstituted, branched or unbranched) having 1-20carbon atoms. In one embodiment, the heteroaliphatic group is optionallysubstituted in a manner that results in the formation of a stablemoiety. Nonlimiting examples of heteroaliphatic moieties arepolyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide,polyglycolide, thioether, ether, alkyl-heterocycle-alkyl,—O-alkyl-O-alkyl, and alkyl-O-haloalkyl.

The term “acyl,” as used herein, represents a hydrogen or an alkyl groupthat is attached to a parent molecular group through a carbonyl group,as defined herein, and is exemplified by formyl (i.e., a carboxyaldehydegroup), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplaryunsubstituted acyl groups include from 1 to 6, from 1 to 11, or from 1to 21 carbons.

The term “alkyl,” as used herein, refers to a branched or straight-chainmonovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbonatoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbonatoms, or 1 to 3 carbon atoms). An “alkylene” is a divalent alkyl group.

The term “alkenyl,” as used herein, alone or in combination with othergroups, refers to a straight chain or branched hydrocarbon residuehaving a carbon-carbon double bond and having 2 to 20 carbon atoms(e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbonatoms). An “alkenylene” is a divalent alkenyl group.

The term “alkynyl,” as used herein, alone or in combination with othergroups, refers to a straight chain or branched hydrocarbon residuehaving a carbon-carbon triple bond and having 2 to 20 carbon atoms(e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbonatoms). An “alkynylene” is a divalent alkynyl group.

The term “amino,” as used herein, represents —N(R^(N1))₂, wherein eachR^(N1) is, independently, H, OH, NO₂, N(R^(N2))₂, SO₂OR^(N2), SO₂R^(N2),SOR^(N2), an N-protecting group, alkyl, alkoxy, aryl, arylalkyl,cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others describedherein), wherein each of these recited R^(N1) groups can be optionallysubstituted; or two R^(N1) combine to form an alkylene orheteroalkylene, and wherein each R^(N2) is, independently, H, alkyl, oraryl. The amino groups of the compounds described herein can be anunsubstituted amino (i.e., —NH₂) or a substituted amino (i.e.,—N(R^(N1))₂).

The term “aryl,” as used herein, refers to an aromatic mono- orpolycarbocyclic radical of, e.g., 6 to 12, carbon atoms having at leastone aromatic ring. Examples of such groups include, but are not limitedto, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl,indanyl, and 1H-indenyl.

The term “arylalkyl,” as used herein, represents an alkyl groupsubstituted with an aryl group. Exemplary unsubstituted arylalkyl groupsare from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons,such as C₁-C₆ alkyl C₆-C₁₀ aryl, C₁-C₁₀ alkyl C₆-C₁₀ aryl, or C₁-C₂₀alkyl C₆-C₁₀ aryl), such as, benzyl and phenethyl. In some embodiments,the alkyl and the aryl each can be further substituted with 1, 2, 3, or4 substituent groups as defined herein for the respective groups.

The term “azido,” as used herein, represents a —N₃ group.

The term “bridged cyclyl,” as used herein, refers to a bridgedpolycyclic group of 5 to 20 atoms, containing from 1 to 3 bridges.Bridged cyclyl includes bridged carbocyclyl (e.g., norbornyl) andbridged heterocyclyl (e.g., 1,4-diazabicyclo[2.2.2]octane).

The term “cyano,” as used herein, represents a —CN group.

The term “carbocyclyl,” as used herein, refers to a non-aromatic C₃-C₁₂,monocyclic or polycyclic (e.g., bicyclic or tricyclic) structure inwhich the rings are formed by carbon atoms. Carbocyclyl structuresinclude cycloalkyl groups (e.g., cyclohexyl) and unsaturated carbocyclylradicals (e.g., cyclohexenyl). Polycyclic carbocyclyl includesspirocyclic carbocyclyl, bridged carbocyclyl, and fused carbocyclyl. A“carbocyclylene” is a divalent carbocyclyl group.

The term “cycloalkyl,” as used herein, refers to a saturated,non-aromatic, monovalent mono- or polycarbocyclic radical of 3 to 10,preferably 3 to 6 carbon atoms. This term is further exemplified byradicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, norbornyl, and adamantyl.

The terms “halo” or “halogen,” as used herein, mean a fluorine (fluoro),chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

The term “heteroalkyl,” as used herein, refers to an alkyl group, asdefined herein, in which one or more of the constituent carbon atomshave been replaced by nitrogen, oxygen, or sulfur. In some embodiments,the heteroalkyl group can be further substituted with 1, 2, 3, or 4substituent groups as described herein for alkyl groups. Examples ofheteroalkyl groups are an “alkoxy” which, as used herein, refers toalkyl-O— (e.g., methoxy and ethoxy), and an “alkylamino” which, as usedherein, refers to —N(alkyl)R^(Na), where R^(Na) is H or alkyl (e.g.,methylamino). A “heteroalkylene” is a divalent heteroalkyl group.

The term “heteroalkenyl,” as used herein, refers to an alkenyl group, asdefined herein, in which one or more of the constituent carbon atomshave been replaced by nitrogen, oxygen, or sulfur. In some embodiments,the heteroalkenyl group can be further substituted with 1, 2, 3, or 4substituent groups as described herein for alkenyl groups. Examples ofheteroalkenyl groups are an “alkenoxy” which, as used herein, refers toalkenyl-O—. A “heteroalkenylene” is a divalent heteroalkenyl group.

The term “heteroalkynyl,” as used herein, refers to an alkynyl group, asdefined herein, in which one or more of the constituent carbon atomshave been replaced by nitrogen, oxygen, or sulfur. In some embodiments,the heteroalkynyl group can be further substituted with 1, 2, 3, or 4substituent groups as described herein for alkynyl groups. Examples ofheteroalkynyl groups are an “alkynoxy” which, as used herein, refers toalkynyl-O—. A “heteroalkynylene” is a divalent heteroalkynyl group.

The term “heteroaryl,” as used herein, refers to an aromatic monocyclicor polycyclic structure of 5 to 12 atoms having at least one aromaticring containing 1, 2, or 3 ring atoms selected from nitrogen, oxygen,and sulfur, with the remaining ring atoms being carbon. One or two ringcarbon atoms of the heteroaryl group may be replaced with a carbonylgroup. Examples of heteroaryl groups are pyridyl, pyrazoyl,benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl,and thiazolyl. A “heteroarylene” is a divalent heteroaryl group.

The term “heteroarylalkyl,” as used herein, represents an alkyl groupsubstituted with a heteroaryl group. Exemplary unsubstitutedheteroarylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 orfrom 7 to 20 carbons, such as C₁-C₆ alkyl C₂-C₉ heteroaryl, C₁-C₁₀ alkylC₂-C₉ heteroaryl, or C₁-C₂₀ alkyl C₂-C₉ heteroaryl). In someembodiments, the alkyl and the heteroaryl each can be furthersubstituted with 1, 2, 3, or 4 substituent groups as defined herein forthe respective groups.

The term “heterocyclyl,” as used herein, refers a monocyclic orpolycyclic radical (e.g., bicyclic or tricyclic) having 3 to 12 atomshaving at least one non-aromatic ring containing 1, 2, 3, or 4 ringatoms selected from N, O, or S, and no aromatic ring containing any N,O, or S atoms. Polycyclic heterocyclyl includes spirocyclicheterocyclyl, bridged heterocyclyl, and fused heterocyclyl. Examples ofheterocyclyl groups include, but are not limited to, morpholinyl,thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl,tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl. A“heterocyclylene” is a divalent heterocyclyl group.

The term “heterocyclylalkyl,” as used herein, represents an alkyl groupsubstituted with a heterocyclyl group. Exemplary unsubstitutedheterocyclylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 orfrom 7 to 20 carbons, such as C₁-C₆ alkyl C₂-C₉ heterocyclyl, C₁-C₁₀alkyl C₂-C₉ heterocyclyl, or C₁-C₂₀ alkyl C₂-C₉ heterocyclyl). In someembodiments, the alkyl and the heterocyclyl each can be furthersubstituted with 1, 2, 3, or 4 substituent groups as defined herein forthe respective groups.

The term “hydroxyalkyl,” as used herein, represents alkyl groupsubstituted with an —OH group.

The term “hydroxyl,” as used herein, represents an —OH group.

The term “imine,” as used herein, represents ═NR^(N) group, where R^(N)is, e.g., H or alkyl.

The term “N-protecting group,” as used herein, represents those groupsintended to protect an amino group against undesirable reactions duringsynthetic procedures. Commonly used N-protecting groups are disclosed inGreene, “Protective Groups in Organic Synthesis,” 3rd Edition (JohnWiley & Sons, New York, 1999). N-protecting groups include, but are notlimited to, acyl, aryloyl, or carbamyl groups such as formyl, acetyl,propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl,trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl,α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotectedD, L, or D, L-amino acids such as alanine, leucine, and phenylalanine;sulfonyl-containing groups such as benzenesulfonyl, andp-toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl,p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,3,5-dimethoxybenzyloxycarbonyl, 2,4-20 dimethoxybenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl,arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl,and silyl groups, such as trimethylsilyl. Preferred N-protecting groupsare alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl,phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl(Cbz).

The term “nitro,” as used herein, represents an —NO₂ group.

The term “oxo,” as used herein, represents an ═O group.

The term “thiol,” as used herein, represents an —SH group.

The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclylgroups may be substituted or unsubstituted. When substituted, there willgenerally be 1 to 4 substituents present, unless otherwise specified.Substituents include, for example: alkyl (e.g., unsubstituted andsubstituted, where the substituents include any group described herein,e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstitutedphenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl),halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted andunsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl,amino (e.g., NH₂ or mono- or dialkyl amino), azido, cyano, nitro, oxo,sulfonyl, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl,and heterocyclyl groups may also be substituted with alkyl(unsubstituted and substituted such as arylalkyl (e.g., substituted andunsubstituted benzyl)).

Compounds described herein (e.g., compounds of the invention) can haveone or more asymmetric carbon atoms and can exist in the form ofoptically pure enantiomers, mixtures of enantiomers such as, forexample, racemates, optically pure diastereoisomers, mixtures ofdiastereoisomers, diastereoisomeric racemates, or mixtures ofdiastereoisomeric racemates. The optically active forms can be obtainedfor example by resolution of the racemates, by asymmetric synthesis orasymmetric chromatography (chromatography with a chiral adsorbent oreluant). That is, certain of the disclosed compounds may exist invarious stereoisomeric forms. Stereoisomers are compounds that differonly in their spatial arrangement. Enantiomers are pairs ofstereoisomers whose mirror images are not superimposable, most commonlybecause they contain an asymmetrically substituted carbon atom that actsas a chiral center. “Enantiomer” means one of a pair of molecules thatare mirror images of each other and are not superimposable.Diastereomers are stereoisomers that are not related as mirror images,most commonly because they contain two or more asymmetricallysubstituted carbon atoms and represent the configuration of substituentsaround one or more chiral carbon atoms. Enantiomers of a compound can beprepared, for example, by separating an enantiomer from a racemate usingone or more well-known techniques and methods, such as, for example,chiral chromatography and separation methods based thereon. Theappropriate technique and/or method for separating an enantiomer of acompound described herein from a racemic mixture can be readilydetermined by those of skill in the art. “Racemate” or “racemic mixture”means a compound containing two enantiomers, wherein such mixturesexhibit no optical activity; i.e., they do not rotate the plane ofpolarized light. “Geometric isomer” means isomers that differ in theorientation of substituent atoms in relationship to a carbon-carbondouble bond, to a cycloalkyl ring, or to a bridged bicyclic system.Atoms (other than H) on each side of a carbon-carbon double bond may bein an E (substituents are on opposite sides of the carbon-carbon doublebond) or Z (substituents are oriented on the same side) configuration.“R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicateconfigurations relative to the core molecule. Certain of the disclosedcompounds may exist in atropisomeric forms. Atropisomers arestereoisomers resulting from hindered rotation about single bonds wherethe steric strain barrier to rotation is high enough to allow for theisolation of the conformers. The compounds described herein (e.g., thecompounds of the invention) may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include forming the salt of a freebase of each isomer of an isomeric pair using an optically active acid(followed by fractional crystallization and regeneration of the freebase), forming the salt of the acid form of each isomer of an isomericpair using an optically active amine (followed by fractionalcrystallization and regeneration of the free acid), forming an ester oramide of each of the isomers of an isomeric pair using an optically pureacid, amine or alcohol (followed by chromatographic separation andremoval of the chiral auxiliary), or resolving an isomeric mixture ofeither a starting material or a final product using various well knownchromatographic methods. When the stereochemistry of a disclosedcompound is named or depicted by structure, the named or depictedstereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weightrelative to the other stereoisomers. When a single enantiomer is namedor depicted by structure, the depicted or named enantiomer is at least60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. When asingle diastereomer is named or depicted by structure, the depicted ornamed diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% byweight pure. Percent optical purity is the ratio of the weight of theenantiomer or over the weight of the enantiomer plus the weight of itsoptical isomer. Diastereomeric purity by weight is the ratio of theweight of one diastereomer or over the weight of all the diastereomers.When the stereochemistry of a disclosed compound is named or depicted bystructure, the named or depicted stereoisomer is at least 60%, 70%, 80%,90%, 99%, or 99.9% by mole fraction pure relative to the otherstereoisomers. When a single enantiomer is named or depicted bystructure, the depicted or named enantiomer is at least 60%, 70%, 80%,90%, 99%, or 99.9% by mole fraction pure. When a single diastereomer isnamed or depicted by structure, the depicted or named diastereomer is atleast 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. Percentpurity by mole fraction is the ratio of the moles of the enantiomer orover the moles of the enantiomer plus the moles of its optical isomer.Similarly, percent purity by moles fraction is the ratio of the moles ofthe diastereomer or over the moles of the diastereomer plus the moles ofits isomer. When a disclosed compound is named or depicted by structurewithout indicating the stereochemistry, and the compound has at leastone chiral center, it is to be understood that the name or structureencompasses either enantiomer of the compound free from thecorresponding optical isomer, a racemic mixture of the compound, ormixtures enriched in one enantiomer relative to its correspondingoptical isomer. When a disclosed compound is named or depicted bystructure without indicating the stereochemistry and has two or morechiral centers, it is to be understood that the name or structureencompasses a diastereomer free of other diastereomers, a number ofdiastereomers free from other diastereomeric pairs, mixtures ofdiastereomers, mixtures of diastereomeric pairs, mixtures ofdiastereomers in which one diastereomer is enriched relative to theother diastereomer(s), or mixtures of diastereomers in which one or morediastereomer is enriched relative to the other diastereomers. Theinvention embraces all of these forms.

Compounds of the present disclosure also include all of the isotopes ofthe atoms occurring in the intermediate or final compounds. “Isotopes”refers to atoms having the same atomic number but different mass numbersresulting from a different number of neutrons in the nuclei. Forexample, isotopes of hydrogen include tritium and deuterium.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. Exemplary isotopes that can be incorporatedinto compounds of the present invention include isotopes of hydrogen,carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P,³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I. Isotopically-labeled compounds(e.g., those labeled with ³H and ¹⁴C) can be useful in compound orsubstrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14(i.e., ¹⁴C) isotopes can be useful for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements). In some embodiments, one or more hydrogenatoms are replaced by ²H or ³H, or one or more carbon atoms are replacedby ¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Preparations ofisotopically labelled compounds are known to those of skill in the art.For example, isotopically labeled compounds can generally be prepared byfollowing procedures analogous to those disclosed for compounds of thepresent invention described herein, by substituting an isotopicallylabeled reagent for a non-isotopically labeled reagent.

As is known in the art, many chemical entities can adopt a variety ofdifferent solid forms such as, for example, amorphous forms orcrystalline forms (e.g., polymorphs, hydrates, solvate). In someembodiments, compounds of the present invention may be utilized in anysuch form, including in any solid form. In some embodiments, compoundsdescribed or depicted herein may be provided or utilized in hydrate orsolvate form.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present disclosure; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

Definitions

In this application, unless otherwise clear from context, (i) the term“a” may be understood to mean “at least one”; (ii) the term “or” may beunderstood to mean “and/or”; and (iii) the terms “including” and“including” may be understood to encompass itemized components or stepswhether presented by themselves or together with one or more additionalcomponents or steps.

As used herein, the terms “about” and “approximately” refer to a valuethat is within 10% above or below the value being described. Forexample, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.

As used herein, the term “administration” refers to the administrationof a composition (e.g., a compound or a preparation that includes acompound as described herein) to a subject or system. Administration toan animal subject (e.g., to a human) may be by any appropriate route.For example, in some embodiments, administration may be bronchial(including by bronchial instillation), buccal, enteral, interdermal,intra-arterial, intradermal, intragastric, intramedullary,intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral,intravenous, intraventricular, mucosal, nasal, oral, rectal,subcutaneous, sublingual, topical, tracheal (including by intratrachealinstillation), transdermal, vaginal, and vitreal.

As used herein, the term “adult soft tissue sarcoma” refers to a sarcomathat develops in the soft tissues of the body, typically in adolescentand adult subjects (e.g., subjects who are at least 10 years old, 11years old, 12 years old, 13 years old, 14 years old, 15 years old, 16years old, 17 years old, 18 years old, or 19 years old). Non-limitingexamples of adult soft tissue sarcoma include, but are not limited to,synovial sarcoma, fibrosarcoma, malignant fibrous histiocytoma,dermatofibrosarcoma, liposarcoma, leiomyosarcoma, hemangiosarcoma,Kaposi's sarcoma, lymphangiosarcoma, malignant peripheral nerve sheathtumor/neurofibrosarcoma, extraskeletal chondrosarcoma, extraskeletalosteosarcoma, extraskeletal myxoid chondrosarcoma, and extraskeletalmesenchymal.

The term “antisense,” as used herein, refers to a nucleic acidcomprising a polynucleotide that is sufficiently complementary to all ora portion of a gene, primary transcript, or processed mRNA, so as tointerfere with expression of the endogenous gene (e.g., BRD9).“Complementary” polynucleotides are those that are capable of basepairing according to the standard Watson-Crick complementarity rules.

Specifically, purines will base pair with pyrimidines to form acombination of guanine paired with cytosine (G:C) and adenine pairedwith either thymine (A:T) in the case of DNA, or adenine paired withuracil (A:U) in the case of RNA. It is understood that twopolynucleotides may hybridize to each other even if they are notcompletely complementary to each other, provided that each has at leastone region that is substantially complementary to the other.

The term “antisense nucleic acid” includes single-stranded RNA as wellas double-stranded DNA expression cassettes that can be transcribed toproduce an antisense RNA. “Active” antisense nucleic acids are antisenseRNA molecules that are capable of selectively hybridizing with a primarytranscript or mRNA encoding a polypeptide having at least 80% sequenceidentity (e.g., 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) with the targetedpolypeptide sequence (e.g., a BRD9 polypeptide sequence). The antisensenucleic acid can be complementary to an entire coding strand, or to onlya portion thereof. In some embodiments, an antisense nucleic acidmolecule is antisense to a “coding region” of the coding strand of anucleotide sequence. The term “coding region” refers to the region ofthe nucleotide sequence comprising codons that are translated into aminoacid residues. In some embodiments, the antisense nucleic acid moleculeis antisense to a “noncoding region” of the coding strand of anucleotide sequence. The term “noncoding region” refers to 5′ and 3′sequences that flank the coding region that are not translated intoamino acids (i.e., also referred to as 5′ and 3′ untranslated regions).The antisense nucleic acid molecule can be complementary to the entirecoding region of mRNA, or can be antisense to only a portion of thecoding or noncoding region of an mRNA. For example, the antisenseoligonucleotide can be complementary to the region surrounding thetranslation start site. An antisense oligonucleotide can be, forexample, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides inlength.

As used herein, the term “BAF complex” refers to the BRG1- orHRBM-associated factors complex in a human cell.

As used herein, the term “BAF complex-related disorder” refers to adisorder that is caused or affected by the level and/or activity of aBAF complex.

As used herein, the terms “GBAF complex” and “GBAF” refer to a SWI/SNFATPase chromatin remodeling complex in a human cell. GBAF complexsubunits may include, but are not limited to, ACTB, ACTL6A, ACTL6B,BICRA, BICRAL, BRD9, SMARCA2, SMARCA4, SMARCC1, SMARCD1, SMARCD2,SMARCD3, and SS18. The term “cancer” refers to a condition caused by theproliferation of malignant neoplastic cells, such as tumors, neoplasms,carcinomas, sarcomas, leukemias, and lymphomas.

As used herein, the term “BRD9” refers to bromodomain-containing protein9, a component of the BAF (BRG1- or BRM-associated factors) complex, aSWI/SNF ATPase chromatin remodeling complex, and belongs to family IV ofthe bromodomain-containing proteins. BRD9 is encoded by the BRD9 gene,the nucleic acid sequence of which is set forth in SEQ ID NO: 1. Theterm “BRD9” also refers to natural variants of the wild-type BRD9protein, such as proteins having at least 85% identity (e.g., 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%identity, or more) to the amino acid sequence of wild-type BRD9, whichis set forth in SEQ ID NO: 2.

As used herein, the term “BRD9-related disorder” refers to a disorderthat is caused or affected by the level and/or activity of BRD9. Theterm “cancer” refers to a condition caused by the proliferation ofmalignant neoplastic cells, such as tumors, neoplasms, carcinomas,sarcomas, leukemias, and lymphomas.

As used herein, a “combination therapy” or “administered in combination”means that two (or more) different agents or treatments are administeredto a subject as part of a defined treatment regimen for a particulardisease or condition. The treatment regimen defines the doses andperiodicity of administration of each agent such that the effects of theseparate agents on the subject overlap. In some embodiments, thedelivery of the two or more agents is simultaneous or concurrent and theagents may be co-formulated. In some embodiments, the two or more agentsare not co-formulated and are administered in a sequential manner aspart of a prescribed regimen. In some embodiments, administration of twoor more agents or treatments in combination is such that the reductionin a symptom, or other parameter related to the disorder is greater thanwhat would be observed with one agent or treatment delivered alone or inthe absence of the other. The effect of the two treatments can bepartially additive, wholly additive, or greater than additive (e.g.,synergistic). Sequential or substantially simultaneous administration ofeach therapeutic agent can be effected by any appropriate routeincluding, but not limited to, oral routes, intravenous routes,intramuscular routes, and direct absorption through mucous membranetissues. The therapeutic agents can be administered by the same route orby different routes. For example, a first therapeutic agent of thecombination may be administered by intravenous injection while a secondtherapeutic agent of the combination may be administered orally.

A “compound of the present invention” and similar terms as used herein,whether explicitly noted or not, refers to compounds useful for treatingBAF-related disorders (e.g., cancer or infection) described herein,including, e.g., compounds of Formula I or Formula II (e.g., compoundsof Table 2A, Table 2B, and Table 2C), as well as salts (e.g.,pharmaceutically acceptable salts), solvates, hydrates, stereoisomers(including atropisomers), and tautomers thereof. Those skilled in theart will appreciate that certain compounds described herein can exist inone or more different isomeric (e.g., stereoisomers, geometric isomers,atropisomers, and tautomers) or isotopic (e.g., in which one or moreatoms has been substituted with a different isotope of the atom, such ashydrogen substituted for deuterium) forms. Unless otherwise indicated orclear from context, a depicted structure can be understood to representany such isomeric or isotopic form, individually or in combination.Compounds described herein can be asymmetric (e.g., having one or morestereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentdisclosure. Cis and trans geometric isomers of the compounds of thepresent disclosure are described and may be isolated as a mixture ofisomers or as separated isomeric forms. In some embodiments, one or morecompounds depicted herein may exist in different tautomeric forms. Aswill be clear from context, unless explicitly excluded, references tosuch compounds encompass all such tautomeric forms. In some embodiments,tautomeric forms result from the swapping of a single bond with anadjacent double bond and the concomitant migration of a proton. Incertain embodiments, a tautomeric form may be a prototropic tautomer,which is an isomeric protonation states having the same empiricalformula and total charge as a reference form. Examples of moieties withprototropic tautomeric forms are ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Insome embodiments, tautomeric forms can be in equilibrium or stericallylocked into one form by appropriate substitution. In certainembodiments, tautomeric forms result from acetal interconversion.

As used herein, the term “degrader” refers to a small molecule compoundincluding a degradation moiety, wherein the compound interacts with aprotein (e.g., BRD9) in a way which results in degradation of theprotein, e.g., binding of the compound results in at least 5% reductionof the level of the protein, e.g., in a cell or subject.

As used herein, the term “degradation moiety” refers to a moiety whosebinding results in degradation of a protein, e.g., BRD9. In one example,the moiety binds to a protease or a ubiquitin ligase that metabolizesthe protein, e.g., BRD9.

By “determining the level of a protein” is meant the detection of aprotein, or an mRNA encoding the protein, by methods known in the arteither directly or indirectly. “Directly determining” means performing aprocess (e.g., performing an assay or test on a sample or “analyzing asample” as that term is defined herein) to obtain the physical entity orvalue. “Indirectly determining” refers to receiving the physical entityor value from another party or source (e.g., a third-party laboratorythat directly acquired the physical entity or value). Methods to measureprotein level generally include, but are not limited to, westernblotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA),radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surfaceplasmon resonance, chemiluminescence, fluorescent polarization,phosphorescence, immunohistochemical analysis, matrix-assisted laserdesorption/ionization time-of-flight (MALDI-TOF) mass spectrometry,liquid chromatography (LC)-mass spectrometry, microcytometry,microscopy, fluorescence activated cell sorting (FACS), and flowcytometry, as well as assays based on a property of a protein including,but not limited to, enzymatic activity or interaction with other proteinpartners. Methods to measure mRNA levels are known in the art.

As used herein, the terms “effective amount,” “therapeutically effectiveamount,” and “a “sufficient amount” of an agent that reduces the leveland/or activity of BRD9 (e.g., in a cell or a subject) described hereinrefer to a quantity sufficient to, when administered to the subject,including a human, effect beneficial or desired results, includingclinical results, and, as such, an “effective amount” or synonym theretodepends on the context in which it is being applied. For example, in thecontext of treating cancer, it is an amount of the agent that reducesthe level and/or activity of BRD9 sufficient to achieve a treatmentresponse as compared to the response obtained without administration ofthe agent that reduces the level and/or activity of BRD9. The amount ofa given agent that reduces the level and/or activity of BRD9 describedherein that will correspond to such an amount will vary depending uponvarious factors, such as the given agent, the pharmaceuticalformulation, the route of administration, the type of disease ordisorder, the identity of the subject (e.g., age, sex, and/or weight) orhost being treated, and the like, but can nevertheless be routinelydetermined by one of skill in the art. Also, as used herein, a“therapeutically effective amount” of an agent that reduces the leveland/or activity of BRD9 of the present disclosure is an amount whichresults in a beneficial or desired result in a subject as compared to acontrol. As defined herein, a therapeutically effective amount of anagent that reduces the level and/or activity of BRD9 of the presentdisclosure may be readily determined by one of ordinary skill by routinemethods known in the art. Dosage regimen may be adjusted to provide theoptimum therapeutic response.

As used herein, the term “inhibitor” refers to any agent which reducesthe level and/or activity of a protein (e.g., BRD9). Non-limitingexamples of inhibitors include small molecule inhibitors, degraders,antibodies, enzymes, or polynucleotides (e.g., siRNA).

The term “inhibitory RNA agent” refers to an RNA, or analog thereof,having sufficient sequence complementarity to a target RNA to direct RNAinterference. Examples also include a DNA that can be used to make theRNA. RNA interference (RNAi) refers to a sequence-specific or selectiveprocess by which a target molecule (e.g., a target gene, protein, orRNA) is down-regulated. Generally, an interfering RNA (“iRNA”) is adouble-stranded short-interfering RNA (siRNA), short hairpin RNA(shRNA), or single-stranded micro-RNA (miRNA) that results in catalyticdegradation of specific mRNAs, and also can be used to lower or inhibitgene expression.

By “level” is meant a level of a protein, or mRNA encoding the protein,as compared to a reference. The reference can be any useful reference,as defined herein. By a “decreased level” or an “increased level” of aprotein is meant a decrease or increase in protein level, as compared toa reference (e.g., a decrease or an increase by about 5%, about 10%,about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90%, about 95%, about 100%, about 150%,about 200%, about 300%, about 400%, about 500%, or more; a decrease oran increase of more than about 10%, about 15%, about 20%, about 50%,about 75%, about 100%, or about 200%, as compared to a reference; adecrease or an increase by less than about 0.01-fold, about 0.02-fold,about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less;or an increase by more than about 1.2-fold, about 1.4-fold, about1.5-fold, about 1.8-fold, about 2.0-fold, about 3.0-fold, about3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold,about 20-fold, about 30-fold, about 40-fold, about 50-fold, about100-fold, about 1000-fold, or more). A level of a protein may beexpressed in mass/vol (e.g., g/dL, mg/mL, μg/mL, ng/mL) or percentagerelative to total protein or mRNA in a sample.

The terms “miRNA” and “microRNA” refer to an RNA agent, preferably asingle-stranded agent, of about 10-50 nucleotides in length, preferablybetween about 15-25 nucleotides in length, which is capable of directingor mediating RNA interference. Naturally-occurring miRNAs are generatedfrom stem-loop precursor RNAs (i.e., pre-miRNAs) by Dicer. The term“Dicer” as used herein, includes Dicer as well as any Dicer ortholog orhomolog capable of processing dsRNA structures into siRNAs, miRNAs,siRNA-like or miRNA-like molecules. The term microRNA (“miRNA”) is usedinterchangeably with the term “small temporal RNA” (“stRNA”) based onthe fact that naturally-occurring miRNAs have been found to be expressedin a temporal fashion (e.g., during development).

By “modulating the activity of a BAF complex,” is meant altering thelevel of an activity related to a BAF complex (e.g., GBAF), or a relateddownstream effect. The activity level of a BAF complex may be measuredusing any method known in the art, e.g., the methods described in Kadochet al, Cell 153:71-85 (2013), the methods of which are hereinincorporated by reference.

“Percent (%) sequence identity” with respect to a referencepolynucleotide or polypeptide sequence is defined as the percentage ofnucleic acids or amino acids in a candidate sequence that are identicalto the nucleic acids or amino acids in the reference polynucleotide orpolypeptide sequence, after aligning the sequences and introducing gaps,if necessary, to achieve the maximum percent sequence identity.Alignment for purposes of determining percent nucleic acid or amino acidsequence identity can be achieved in various ways that are within thecapabilities of one of skill in the art, for example, using publiclyavailable computer software such as BLAST, BLAST-2, or Megalignsoftware. Those skilled in the art can determine appropriate parametersfor aligning sequences, including any algorithms needed to achievemaximal alignment over the full length of the sequences being compared.For example, percent sequence identity values may be generated using thesequence comparison computer program BLAST. As an illustration, thepercent sequence identity of a given nucleic acid or amino acidsequence, A, to, with, or against a given nucleic acid or amino acidsequence, B, (which can alternatively be phrased as a given nucleic acidor amino acid sequence, A that has a certain percent sequence identityto, with, or against a given nucleic acid or amino acid sequence, B) iscalculated as follows:

100 multiplied by (the fraction X/Y)

where X is the number of nucleotides or amino acids scored as identicalmatches by a sequence alignment program (e.g., BLAST) in that program'salignment of A and B, and where Y is the total number of nucleic acidsin B. It will be appreciated that where the length of nucleic acid oramino acid sequence A is not equal to the length of nucleic acid oramino acid sequence B, the percent sequence identity of A to B will notequal the percent sequence identity of B to A.

A “pharmaceutically acceptable excipient,” as used herein, refers anyingredient other than the compounds described herein (for example, avehicle capable of suspending or dissolving the active compound) andhaving the properties of being substantially nontoxic andnon-inflammatory in a patient. Excipients may include, for example:antiadherents, antioxidants, binders, coatings, compression aids,disintegrants, dyes (colors), emollients, emulsifiers, fillers(diluents), film formers or coatings, flavors, fragrances, glidants(flow enhancers), lubricants, preservatives, printing inks, sorbents,suspensing or dispersing agents, sweeteners, and waters of hydration.Exemplary excipients include, but are not limited to: butylatedhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic),calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone,citric acid, crospovidone, cysteine, ethylcellulose, gelatin,hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose,magnesium stearate, maltitol, mannitol, methionine, methylcellulose,methyl paraben, microcrystalline cellulose, polyethylene glycol,polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben,retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch(corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A,vitamin E, vitamin C, and xylitol.

As used herein, the term “pharmaceutically acceptable salt” means anypharmaceutically acceptable salt of the compound of any of the compoundsdescribed herein. For example, pharmaceutically acceptable salts of anyof the compounds described herein include those that are within thescope of sound medical judgment, suitable for use in contact with thetissues of humans and animals without undue toxicity, irritation,allergic response and are commensurate with a reasonable benefit/riskratio. Pharmaceutically acceptable salts are well known in the art. Forexample, pharmaceutically acceptable salts are described in: Berge etal., J. Pharmaceutical Sciences 66:1-19, 1977 and in PharmaceuticalSalts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G.Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during thefinal isolation and purification of the compounds described herein orseparately by reacting a free base group with a suitable organic acid.

The compounds described herein may have ionizable groups so as to becapable of preparation as pharmaceutically acceptable salts. These saltsmay be acid addition salts involving inorganic or organic acids or thesalts may, in the case of acidic forms of the compounds describedherein, be prepared from inorganic or organic bases. Frequently, thecompounds are prepared or used as pharmaceutically acceptable saltsprepared as addition products of pharmaceutically acceptable acids orbases. Suitable pharmaceutically acceptable acids and bases and methodsfor preparation of the appropriate salts are well-known in the art.Salts may be prepared from pharmaceutically acceptable non-toxic acidsand bases including inorganic and organic acids and bases.Representative acid addition salts include acetate, adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, toluenesulfonate, undecanoate, and valeratesalts. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, and magnesium, as well as nontoxicammonium, quaternary ammonium, and amine cations, including, but notlimited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, andethylamine.

The term “pharmaceutical composition,” as used herein, represents acomposition containing a compound described herein formulated with apharmaceutically acceptable excipient, and manufactured or sold with theapproval of a governmental regulatory agency as part of a therapeuticregimen for the treatment of disease in a mammal. Pharmaceuticalcompositions can be formulated, for example, for oral administration inunit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup);for topical administration (e.g., as a cream, gel, lotion, or ointment);for intravenous administration (e.g., as a sterile solution free ofparticulate emboli and in a solvent system suitable for intravenoususe); or in any other pharmaceutically acceptable formulation.

By “reducing the activity of BRD9,” is meant decreasing the level of anactivity related to an BRD9, or a related downstream effect. Anon-limiting example of inhibition of an activity of BRD9 is decreasingthe level of a BAF complex (e.g., GBAF) in a cell. The activity level ofBRD9 may be measured using any method known in the art. In someembodiments, an agent which reduces the activity of BRD9 is a smallmolecule BRD9 inhibitor. In some embodiments, an agent which reduces theactivity of BRD9 is a small molecule BRD9 degrader.

By “reducing the level of BRD9,” is meant decreasing the level of BRD9in a cell or subject. The level of BRD9 may be measured using any methodknown in the art.

By a “reference” is meant any useful reference used to compare proteinor mRNA levels. The reference can be any sample, standard, standardcurve, or level that is used for comparison purposes. The reference canbe a normal reference sample or a reference standard or level. A“reference sample” can be, for example, a control, e.g., a predeterminednegative control value such as a “normal control” or a prior sampletaken from the same subject; a sample from a normal healthy subject,such as a normal cell or normal tissue; a sample (e.g., a cell ortissue) from a subject not having a disease; a sample from a subjectthat is diagnosed with a disease, but not yet treated with a compounddescribed herein; a sample from a subject that has been treated by acompound described herein; or a sample of a purified protein (e.g., anydescribed herein) at a known normal concentration. By “referencestandard or level” is meant a value or number derived from a referencesample. A “normal control value” is a pre-determined value indicative ofnon-disease state, e.g., a value expected in a healthy control subject.Typically, a normal control value is expressed as a range (“between Xand Y”), a high threshold (“no higher than X”), or a low threshold (“nolower than X”). A subject having a measured value within the normalcontrol value for a particular biomarker is typically referred to as“within normal limits” for that biomarker. A normal reference standardor level can be a value or number derived from a normal subject nothaving a disease or disorder (e.g., cancer); a subject that has beentreated with a compound described herein. In preferred embodiments, thereference sample, standard, or level is matched to the sample subjectsample by at least one of the following criteria: age, weight, sex,disease stage, and overall health. A standard curve of levels of apurified protein, e.g., any described herein, within the normalreference range can also be used as a reference.

The terms “short interfering RNA” and “siRNA” (also known as “smallinterfering RNAs”) refer to an RNA agent, preferably a double-strandedagent, of about 10-50 nucleotides in length, the strands optionallyhaving overhanging ends comprising, for example 1, 2 or 3 overhangingnucleotides (or nucleotide analogs), which is capable of directing ormediating RNA interference. Naturally-occurring siRNAs are generatedfrom longer dsRNA molecules (e.g., >25 nucleotides in length) by acell's RNAi machinery (e.g., Dicer or a homolog thereof).

The term “shRNA”, as used herein, refers to an RNA agent having astem-loop structure, comprising a first and second region ofcomplementary sequence, the degree of complementarity and orientation ofthe regions being sufficient such that base pairing occurs between theregions, the first and second regions being joined by a loop region, theloop resulting from a lack of base pairing between nucleotides (ornucleotide analogs) within the loop region.

As used herein, the term “subject” refers to any organism to which acomposition in accordance with the invention may be administered, e.g.,for experimental, diagnostic, prophylactic, and/or therapeutic purposes.Typical subjects include any animal (e.g., mammals such as mice, rats,rabbits, non-human primates, and humans). A subject may seek or be inneed of treatment, require treatment, be receiving treatment, bereceiving treatment in the future, or be a human or animal who is undercare by a trained professional for a particular disease or condition.

As used herein, the term “SS18-SSX fusion protein-related disorder”refers to a disorder that is caused or affected by the level and/oractivity of SS18-SSX fusion protein.

As used herein, the terms “treat,” “treated,” or “treating” mean boththerapeutic treatment and prophylactic or preventative measures whereinthe object is to prevent or slow down (lessen) an undesiredphysiological condition, disorder, or disease, or obtain beneficial ordesired clinical results. Beneficial or desired clinical resultsinclude, but are not limited to, alleviation of symptoms; diminishmentof the extent of a condition, disorder, or disease; stabilized (i.e.,not worsening) state of condition, disorder, or disease; delay in onsetor slowing of condition, disorder, or disease progression; ameliorationof the condition, disorder, or disease state or remission (whetherpartial or total), whether detectable or undetectable; an ameliorationof at least one measurable physical parameter, not necessarilydiscernible by the patient; or enhancement or improvement of condition,disorder, or disease. Treatment includes eliciting a clinicallysignificant response without excessive levels of side effects. Treatmentalso includes prolonging survival as compared to expected survival ifnot receiving treatment.

As used herein, the terms “variant” and “derivative” are usedinterchangeably and refer to naturally-occurring, synthetic, andsemi-synthetic analogues of a compound, peptide, protein, or othersubstance described herein. A variant or derivative of a compound,peptide, protein, or other substance described herein may retain orimprove upon the biological activity of the original material.

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objects, and advantages of theinvention will be apparent from the description and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a series of graphs illustrating the effect of specific guideRNA (sgRNA) targeting of the BRD9 BAF complex subunit on synovialsarcoma cell growth. The Y-axis indicated the dropout ratio. The X-axisindicates the nucleotide position of the BRD9 gene. The grey boxindicates the range of the negative control sgRNAs in the screen. TheSYO1 cell line carries SS18-SSX2 fusion protein. The breakpoint joiningthe N-terminal region of SS18 to the C-terminal region of SSX2 areindicated by the black lines in their respective panel. The linearprotein sequence is show with BRD9 PFAM domains annotated from the PFAMdatabase.

FIG. 2 is an image illustrating dose dependent depletion of BRD9 levelsin a synovial sarcoma cell line (SYO1) in the presence of a BRD9degrader.

FIG. 3 is an image illustrating sustained suppression of BRD9 levels ina synovial sarcoma cell line (SYO1) in the presence of a BRD9 degraderover 72 hours.

FIG. 4 is an image illustrating sustained suppression of BRD9 levels intwo cell lines (293T and SYO1) in the presence of a BRD9 degrader over 5days.

FIG. 5 is an image illustrating sustained suppression of BRD9 levels insynovial sarcoma cell lines (SYO1 and Yamato) in the presence of a BRD9degrader over 7 days compared to the levels in cells treated with CRISPRreagents.

FIG. 6 is an image illustrating the effect on cell growth of six celllines (SYO1, Yamato, A549, HS-SY-II, ASKA, and 293T) in the presence ofa BRD9 degrader and a BRD9 inhibitor.

FIG. 7 is an image illustrating the effect on cell growth of two celllines (SYO1 and G401) in the presence of a BRD9 degrader.

FIG. 8 is an image illustrating the effect on cell growth of threesynovial sarcoma cell lines (SYO1, HS-SY-II, and ASKA) in the presenceof a BRD9 degrader, BRD9 binder and E3 ligase binder.

FIG. 9 is an image illustrating the effect on cell growth of threenon-synovial sarcoma cell lines (RD, HCT116, and Calu6) in the presenceof a BRD9 degrader, BRD9 binder and E3 ligase binder.

FIG. 10 is a graph illustrating the percentage of SYO1 in various cellcycle phases following treatment with DMSO, Compound 1 at 200 nM, orCompound 1 at 1 μM for 8 or 13 days.

FIG. 11 is a series of contour plots illustrating the percentage of SYO1cells in various cell cycle phases following treatment with DMSO,Compound 1 at 200 nM, Compound 1 at 1 μM, or lenalidomide at 200 nM for8 days. Numerical values corresponding to each contour plot are found inthe table below.

FIG. 12 is a series of contour plots illustrating the percentage of SYO1cells in various cell cycle phases following treatment with DMSO,Compound 1 at 200 nM, Compound 1 at 1 μM, or lenalidomide at 200 nM for13 days. Numerical values corresponding to each contour plot are foundin the table below.

FIG. 13 is a series of contour plots illustrating the percentage ofearly- and late-apoptotic SYO1 cells following treatment with DMSO,Compound 1 at 200 nM, Compound 1 at 1 μM, or lenalidomide at 200 nM for8 days. Numerical values corresponding to each contour plot are found inthe table below.

FIG. 14 is a graph illustrating the proteins present in BAF complexesincluding the SS18-SSX fusion protein.

DETAILED DESCRIPTION

The present disclosure features compositions and methods useful for thetreatment of BAF-related disorders (e.g., cancer and infection). Thedisclosure further features compositions and methods useful forinhibition of the level and/or activity of BRD9, e.g., for the treatmentof disorders such as cancer (e.g., sarcoma) and infection (e.g., viralinfection), e.g., in a subject in need thereof.

Compounds

Compounds described herein reduce the level of an activity related toBRD9, or a related downstream effect, or reduce the level of BRD9 in acell or subject. Exemplary compounds described herein have the structureaccording to Formula I or Formula II.

Formula I is:

where

R¹ is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₂-C₆ alkenyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₁₀ carbocyclyl;

Z¹ is CR² or N;

R² is H, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉ heteroaryl;

X¹ is a bond, O, NR^(3a),

or CR^(4a)R^(5a);

X² is O, NR^(3b),

or CR^(4b)R^(5b);

X³ is O, NR^(3c),

or CR^(4c)R^(5c);

X⁴ is a bond, O, NR^(3d),

or CR^(4d)R^(5d);

X⁵ is O or NR^(3e) and X⁶ is CR^(4f)R^(5f), or X⁵ is CR^(4e)R^(5e) andX⁶ is O or NR^(3f);

X⁷ is O, NR^(3g), or CR^(4g)R^(5g);

X⁸ is O, NR^(3h), or CR^(4h)R^(5h);

each of R^(3a), R^(3b), R^(3c), and R^(3d) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3a) and R^(4b), R^(4a) and R^(3b), R^(4b) andR^(4a), R^(3b) and R^(4c), R^(4b) and R^(4c), R^(3c) and R^(4b), R^(3c)and R^(4d), R^(4c) and R^(4d), and/or R^(3d) and R^(4c), together withthe atoms to which each is attached, combine to form optionallysubstituted C₂-C₉ heterocyclyl;

each of R^(4a), R^(4b), R^(4c), and R^(4d) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, or optionally substituted amino, or R^(3a) andR^(4b), R^(4a) and R^(3b), R^(4b) and R^(4a), R^(3b) and R^(4c), R^(4b)and R^(4c), R^(3c) and R^(4b), R^(3c) and R^(4d), R^(4c) and R^(4d),and/or R^(3d) and R^(4c), together with the atoms to which each isattached, combine to form optionally substituted C₂-C₉ heterocyclyl;

each of R^(5a), R^(5b), R^(5c), and R^(5d) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino;

each of R^(3e), R^(3f), R^(3g), and R^(3h) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3e) and R^(4f) or R^(4e) and R^(3f), togetherwith the atoms to which each is attached, combine to form optionallysubstituted heterocyclycl;

each of R^(4e), R^(4f), R^(4g), and R^(4h) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3e) and R^(4f) or R^(4e) and R^(3f), togetherwith the atoms to which each is attached, combine to form optionallysubstituted heterocyclycl;

each of R^(5e), R^(5f), R^(5g), and R^(5h) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; and

G is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, or a pharmaceutically acceptable salt thereof.

Formula II is:

A-L-B   Formula II,

where

B is a degradation moiety,

L is a linker, and

A has the structure of Formula III:

where

R¹ is H, optionally substituted C₁-C₆ alkyl, optionally substitutedC₂-C₆ alkenyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₁₀ carbocyclyl;

Z¹ is CR² or N;

R² is H, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, or optionally substituted C₂-C₉ heteroaryl;

X¹′ is a bond, O, NR^(3a)′, or CR^(4a)′R^(5a)′;

X²′ is O, NR^(3b)′, or CR^(4b)′R^(5b)′;

X³′ is O, NR^(3c)′, or CR^(4c)′R^(5c)′;

X⁴′ is a bond, O, NR^(3d)′, or CR^(4d)′R^(5d)′;

X⁵′ is O, NR^(3e)′, or CR^(4e)′R^(5e)′;

X⁶′ is O, NR^(3f)′, or CR^(4f)′R^(5f)′;

X⁷′ is O, NR^(3g)′, or CR^(4g)′R⁵⁹′;

each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is, independently, H,

halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3a)′ and R^(4b)′, R^(4a)′ and R^(3b)′, R^(4b)′and R^(4a)′, R^(3b)′ and R^(4c)′, R^(4b)′ and R^(4c)′, R^(3c)′ andR^(4b)′, R^(3c)′ and R^(4d)′, R^(4c)′ and R^(4d)′, and/or R^(3d)′ andR^(4c)′, together with the atoms to which each is attached, combine toform optionally substituted C₂-C₉ heterocyclyl;

R³′ is absent, optionally substituted C₁-C₆ alkylene, optionallysubstituted C₁-C₆ heteroalkylene, optionally substituted C₃-C₁₀carbocyclylene, optionally substituted C₂-C₉ heterocyclylene, optionallysubstituted C₆-C₁₀ arylene, optionally substituted C₂-C₉ heteroarylene,optionally substituted C₂-C₆ alkenylene, optionally substituted C₂-C₆heteroalkenylene, optionally substituted sulfone, optionally substitutedsulfonamide, or optionally substituted amino;

each of R^(4a)′, R^(4b)′, R^(4c)′, and R^(4d)′ is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, thiol, optionally substituted sulfone, or optionallysubstituted amino, or R^(3a)′ and R^(4b), R^(4a)′ and R^(3b)′, R^(4b)′and R^(4a)′, R^(3b)′ and R^(4c)′, R^(4b)′ and R^(4c)′, R^(3c)′ andR^(4b)′, R^(3c)′ and R^(4d)′, R^(4c)′ and R^(4d)′, and/or R^(3d)′ andR^(4c)′, together with the atoms to which each is attached, combine toform optionally substituted C₂-C₉ heterocyclyl;

each of R^(5a)′, R^(5b)′, R^(5c)′, and R^(5d)′ is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino;

each of R^(3e)′, R^(3f)′, and R^(3g)′ is, independently, H,

halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3e) and R^(4f) or R^(4e) and R^(3f), togetherwith the atoms to which each is attached, combine to form optionallysubstituted heterocyclycl;

each of R^(4e)′, R^(4f)′, and R^(4g)′ is, independently, H, halogen,hydroxyl, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted C₁-C₆ acyl, thiol, optionally substituted sulfone,optionally substituted sulfonamide, or optionally substituted amino, orR^(3e)′ and R^(4f)′ or R^(4e)′ and R^(3f)′, together with the atoms towhich each is attached, combine to form optionally substitutedheterocyclycl;

each of R^(5e)′, R^(5f)′, and R^(5g)′ is, independently, H, halogen,hydroxyl, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, hydroxyl, thiol, oroptionally substituted amino;

G″ is

optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl;

G′ is optionally substituted C₃-C₁₀ carbocyclylene, C₂-C₉heterocyclylene, optionally substituted C₆-C₁₀ arylene, or optionallysubstituted C₂-C₉ heteroarylene; and

A¹ is a bond between A and the linker,

where one of R^(3a)′, R^(3b)′, R^(3c)′, R^(3d)′, R^(3e)′, R^(3f)′, andR^(3g)′ is

or G is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure of any one ofcompounds D1-D38 in Table 2A, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound has the structure of any oneof compounds D39-D302 in Table 2B, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound has the structure of any oneof compounds D303-D375 in Table 2C, or a pharmaceutically acceptablesalt thereof.

Other embodiments, as well as exemplary methods for the synthesis ofproduction of these compounds, are described herein.

Pharmaceutical Uses

The compounds described herein are useful in the methods of theinvention and, while not bound by theory, are believed to exert theirdesirable effects through their ability to modulate the level, status,and/or activity of a BAF complex, e.g., by inhibiting the activity orlevel of the BRD9 protein in a cell within the BAF complex in a mammal.

An aspect of the present invention relates to methods of treatingdisorders related to BRD9 such as cancer in a subject in need thereof.In some embodiments, the compound is administered in an amount and for atime effective to result in one of (or more, e.g., two or more, three ormore, four or more of): (a) reduced tumor size, (b) reduced rate oftumor growth, (c) increased tumor cell death (d) reduced tumorprogression, (e) reduced number of metastases, (f) reduced rate ofmetastasis, (g) decreased tumor recurrence (h) increased survival ofsubject, and (i) increased progression free survival of a subject.

Treating cancer can result in a reduction in size or volume of a tumor.For example, after treatment, tumor size is reduced by 5% or greater(e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relativeto its size prior to treatment. Size of a tumor may be measured by anyreproducible means of measurement. For example, the size of a tumor maybe measured as a diameter of the tumor.

Treating cancer may further result in a decrease in number of tumors.For example, after treatment, tumor number is reduced by 5% or greater(e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relativeto number prior to treatment. Number of tumors may be measured by anyreproducible means of measurement, e.g., the number of tumors may bemeasured by counting tumors visible to the naked eye or at a specifiedmagnification (e.g., 2×, 3×, 4×, 5×, 10×, or 50×).

Treating cancer can result in a decrease in number of metastatic nodulesin other tissues or organs distant from the primary tumor site. Forexample, after treatment, the number of metastatic nodules is reduced by5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% orgreater) relative to number prior to treatment. The number of metastaticnodules may be measured by any reproducible means of measurement. Forexample, the number of metastatic nodules may be measured by countingmetastatic nodules visible to the naked eye or at a specifiedmagnification (e.g., 2×, 10×, or 50×).

Treating cancer can result in an increase in average survival time of apopulation of subjects treated according to the present invention incomparison to a population of untreated subjects. For example, theaverage survival time is increased by more than 30 days (more than 60days, 90 days, or 120 days). An increase in average survival time of apopulation may be measured by any reproducible means. An increase inaverage survival time of a population may be measured, for example, bycalculating for a population the average length of survival followinginitiation of treatment with the compound described herein. An increasein average survival time of a population may also be measured, forexample, by calculating for a population the average length of survivalfollowing completion of a first round of treatment with apharmaceutically acceptable salt of a compound described herein.

Treating cancer can also result in a decrease in the mortality rate of apopulation of treated subjects in comparison to an untreated population.For example, the mortality rate is decreased by more than 2% (e.g., morethan 5%, 10%, or 25%). A decrease in the mortality rate of a populationof treated subjects may be measured by any reproducible means, forexample, by calculating for a population the average number ofdisease-related deaths per unit time following initiation of treatmentwith a pharmaceutically acceptable salt of a compound described herein.A decrease in the mortality rate of a population may also be measured,for example, by calculating for a population the average number ofdisease-related deaths per unit time following completion of a firstround of treatment with a pharmaceutically acceptable salt of a compounddescribed herein.

Combination Therapies

A method of the invention can be used alone or in combination with anadditional therapeutic agent, e.g., other agents that treat cancer orsymptoms associated therewith, or in combination with other types oftherapies to treat cancer. In combination treatments, the dosages of oneor more of the therapeutic compounds may be reduced from standarddosages when administered alone. For example, doses may be determinedempirically from drug combinations and permutations or may be deduced byisobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)).In this case, dosages of the compounds when combined should provide atherapeutic effect.

In some embodiments, the second therapeutic agent is a chemotherapeuticagent (e.g., a cytotoxic agent or other chemical compound useful in thetreatment of cancer). These include alkylating agents, antimetabolites,folic acid analogs, pyrimidine analogs, purine analogs and relatedinhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics,L-Asparaginase, topoisomerase inhibitors, interferons, platinumcoordination complexes, anthracenedione substituted urea, methylhydrazine derivatives, adrenocortical suppressant,adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens,antiandrogen, and gonadotropin-releasing hormone analog. Also includedis 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin,capecitabine, paclitaxel, and doxetaxel. Non-limiting examples ofchemotherapeutic agents include alkylating agents such as thiotepa andcyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, trietylenephosphoramide,triethiylenethiophosphoramide and trimethylolomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analogue topotecan); bryostatin; callystatin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); cryptophycins (particularly cryptophycin 1 and cryptophycin8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin;spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gammaII and calicheamicinomegaII (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994));dynemicin, including dynemicin A; bisphosphonates, such as clodronate;an esperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antiobiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®(doxorubicin, including morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin,mitomycins such as mitomycin C, mycophenolic acid, nogalamycin,olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL®(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE®,cremophor-free, albumin-engineered nanoparticle formulation ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil;GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum coordination complexes such as cisplatin, oxaliplatin andcarboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide;mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone;teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate;irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO); retinoids such as retinoic acid;capecitabine; and pharmaceutically acceptable salts, acids orderivatives of any of the above. Two or more chemotherapeutic agents canbe used in a cocktail to be administered in combination with the firsttherapeutic agent described herein. Suitable dosing regimens ofcombination chemotherapies are known in the art and described in, forexample, Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), andDouillard et al., Lancet 355(9209):1041-1047 (2000).

In some embodiments, the second therapeutic agent is a therapeutic agentwhich is a biologic such a cytokine (e.g., interferon or an interleukin(e.g., IL-2)) used in cancer treatment. In some embodiments the biologicis an anti-angiogenic agent, such as an anti-VEGF agent, e.g.,bevacizumab (AVASTIN®). In some embodiments the biologic is animmunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., ahumanized antibody, a fully human antibody, an Fc fusion protein or afunctional fragment thereof) that agonizes a target to stimulate ananti-cancer response, or antagonizes an antigen important for cancer.Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab);SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab);HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH®(alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab);XOLAIR® (omalizumab); BEXXAR® (tositumomab-I-131); RAPTIVA®(efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI®(natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab);LUCENTIS® (ranibizumab); SOLIRIS® (eculizumab); CIMZIA® (certolizumabpegol); SIMPONI® (golimumab); ILARIS® (canakinumab); STELARA®(ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab); NUMAX®(motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab); YERVOY®(ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA® (pertuzumab);KADCYLA® (ado-trastuzumab emtansine); and GAZYVA® (obinutuzumab). Alsoincluded are antibody-drug conjugates.

The second agent may be a therapeutic agent which is a non-drugtreatment. For example, the second therapeutic agent is radiationtherapy, cryotherapy, hyperthermia, and/or surgical excision of tumortissue.

The second agent may be a checkpoint inhibitor. In one embodiment, theinhibitor of checkpoint is an inhibitory antibody (e.g., a monospecificantibody such as a monoclonal antibody). The antibody may be, e.g.,humanized or fully human. In some embodiments, the inhibitor ofcheckpoint is a fusion protein, e.g., an Fc-receptor fusion protein. Insome embodiments, the inhibitor of checkpoint is an agent, such as anantibody, that interacts with a checkpoint protein. In some embodiments,the inhibitor of checkpoint is an agent, such as an antibody, thatinteracts with the ligand of a checkpoint protein. In some embodiments,the inhibitor of checkpoint is an inhibitor (e.g., an inhibitoryantibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4antibody or fusion a protein such as ipilimumab/YERVOY® ortremelimumab). In some embodiments, the inhibitor of checkpoint is aninhibitor (e.g., an inhibitory antibody or small molecule inhibitor) ofPD-1 (e.g., nivolumab/OPDIVO®; pembrolizumab/KEYTRUDA®;pidilizumab/CT-011). In some embodiments, the inhibitor of checkpoint isan inhibitor (e.g., an inhibitory antibody or small molecule inhibitor)of PDL1 (e.g., MPDL3280A/R^(G7446); MEDI4736; MSB0010718C; BMS 936559).In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g.,an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2(e.g., a PDL2/Ig fusion protein such as AMP 224). In some embodiments,the inhibitor of checkpoint is an inhibitor (e.g., an inhibitoryantibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4,BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1,CHK2, A2aR, B-7 family ligands, or a combination thereof.

In some embodiments, the anti-cancer therapy is a T cell adoptivetransfer (ACT) therapy. In some embodiments, the T cell is an activatedT cell. The T cell may be modified to express a chimeric antigenreceptor (CAR). CAR modified T (CAR-T) cells can be generated by anymethod known in the art. For example, the CAR-T cells can be generatedby introducing a suitable expression vector encoding the CAR to a Tcell. Prior to expansion and genetic modification of the T cells, asource of T cells is obtained from a subject. T cells can be obtainedfrom a number of sources, including peripheral blood mononuclear cells,bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from asite of infection, ascites, pleural effusion, spleen tissue, and tumors.In certain embodiments of the present invention, any number of T celllines available in the art, may be used. In some embodiments, the T cellis an autologous T cell. Whether prior to or after genetic modificationof the T cells to express a desirable protein (e.g., a CAR), the T cellscan be activated and expanded generally using methods as described, forexample, in U.S. Pat. Nos. 6,352,694; 6,534,055; 6,905,680; 6,692,964;5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869;7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; andU.S. Patent Application Publication No. 20060121005.

In any of the combination embodiments described herein, the first andsecond therapeutic agents are administered simultaneously orsequentially, in either order. The first therapeutic agent may beadministered immediately, up to 1 hour, up to 2 hours, up to 3 hours, upto 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours,up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours upto 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after thesecond therapeutic agent.

Pharmaceutical Compositions

The pharmaceutical compositions described herein are preferablyformulated into pharmaceutical compositions for administration to humansubjects in a biologically compatible form suitable for administrationin vivo.

The compounds described herein may be used in the form of the free base,in the form of salts, solvates, and as prodrugs. All forms are withinthe methods described herein. In accordance with the methods of theinvention, the described compounds or salts, solvates, or prodrugsthereof may be administered to a patient in a variety of forms dependingon the selected route of administration, as will be understood by thoseskilled in the art. The compounds described herein may be administered,for example, by oral, parenteral, buccal, sublingual, nasal, rectal,patch, pump, intratumoral, or transdermal administration and thepharmaceutical compositions formulated accordingly. Parenteraladministration includes intravenous, intraperitoneal, subcutaneous,intramuscular, transepithelial, nasal, intrapulmonary, intrathecal,rectal, and topical modes of administration. Parenteral administrationmay be by continuous infusion over a selected period of time.

A compound described herein may be orally administered, for example,with an inert diluent or with an assimilable edible carrier, or it maybe enclosed in hard or soft shell gelatin capsules, or it may becompressed into tablets, or it may be incorporated directly with thefood of the diet. For oral therapeutic administration, a compounddescribed herein may be incorporated with an excipient and used in theform of ingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, and wafers. A compound described herein may also beadministered parenterally. Solutions of a compound described herein canbe prepared in water suitably mixed with a surfactant, such ashydroxypropylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, DMSO, and mixtures thereof with or withoutalcohol, and in oils. Under ordinary conditions of storage and use,these preparations may contain a preservative to prevent the growth ofmicroorganisms. Conventional procedures and ingredients for theselection and preparation of suitable formulations are described, forexample, in Remington's Pharmaceutical Sciences (2012, 22nd ed.) and inThe United States Pharmacopeia: The National Formulary (USP 41 NF36),published in 2018. The pharmaceutical forms suitable for injectable useinclude sterile aqueous solutions or dispersions and sterile powders forthe extemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that may be easily administered via syringe. Compositions fornasal administration may conveniently be formulated as aerosols, drops,gels, and powders. Aerosol formulations typically include a solution orfine suspension of the active substance in a physiologically acceptableaqueous or non-aqueous solvent and are usually presented in single ormultidose quantities in sterile form in a sealed container, which cantake the form of a cartridge or refill for use with an atomizing device.Alternatively, the sealed container may be a unitary dispensing device,such as a single dose nasal inhaler or an aerosol dispenser fitted witha metering valve which is intended for disposal after use. Where thedosage form includes an aerosol dispenser, it will contain a propellant,which can be a compressed gas, such as compressed air or an organicpropellant, such as fluorochlorohydrocarbon. The aerosol dosage formscan also take the form of a pump-atomizer. Compositions suitable forbuccal or sublingual administration include tablets, lozenges, andpastilles, where the active ingredient is formulated with a carrier,such as sugar, acacia, tragacanth, gelatin, and glycerine. Compositionsfor rectal administration are conveniently in the form of suppositoriescontaining a conventional suppository base, such as cocoa butter. Acompound described herein may be administered intratumorally, forexample, as an intratumoral injection. Intratumoral injection isinjection directly into the tumor vasculature and is specificallycontemplated for discrete, solid, accessible tumors. Local, regional, orsystemic administration also may be appropriate. A compound describedherein may advantageously be contacted by administering an injection ormultiple injections to the tumor, spaced for example, at approximately,1 cm intervals. In the case of surgical intervention, the presentinvention may be used preoperatively, such as to render an inoperabletumor subject to resection. Continuous administration also may beapplied where appropriate, for example, by implanting a catheter into atumor or into tumor vasculature.

The compounds described herein may be administered to an animal, e.g., ahuman, alone or in combination with pharmaceutically acceptablecarriers, as noted herein, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration, and standard pharmaceutical practice.

Dosages

The dosage of the compounds described herein, and/or compositionsincluding a compound described herein, can vary depending on manyfactors, such as the pharmacodynamic properties of the compound; themode of administration; the age, health, and weight of the recipient;the nature and extent of the symptoms; the frequency of the treatment,and the type of concurrent treatment, if any; and the clearance rate ofthe compound in the animal to be treated. One of skill in the art candetermine the appropriate dosage based on the above factors. Thecompounds described herein may be administered initially in a suitabledosage that may be adjusted as required, depending on the clinicalresponse. In general, satisfactory results may be obtained when thecompounds described herein are administered to a human at a daily dosageof, for example, between 0.05 mg and 3000 mg (measured as the solidform). Dose ranges include, for example, between 10-1000 mg (e.g.,50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400,450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of thecompound is administered.

Alternatively, the dosage amount can be calculated using the body weightof the patient. For example, the dose of a compound, or pharmaceuticalcomposition thereof, administered to a patient may range from 0.1-100mg/kg (e.g., 0.1-50 mg/kg (e.g., 0.25-25 mg/kg)). In exemplary,non-limiting embodiments, the dose may range from 0.5-5.0 mg/kg (e.g.,0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg/kg) or from5.0-20 mg/kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg).

Kits

The invention also features kits including (a) a pharmaceuticalcomposition including an agent that reduces the level and/or activity ofBRD9 in a cell or subject described herein, and (b) a package insertwith instructions to perform any of the methods described herein. Insome embodiments, the kit includes (a) a pharmaceutical compositionincluding an agent that reduces the level and/or activity of BRD9 in acell or subject described herein, (b) an additional therapeutic agent(e.g., an anti-cancer agent), and (c) a package insert with instructionsto perform any of the methods described herein.

EXAMPLES Example 1—High Density Tiling sgRNA Screen Against Human BAFComplex Subunits in Synovial Sarcoma Cell Line SYO1

The following example shows that BRD9 sgRNA inhibits cell growth insynovial sarcoma cells.

Procedure: To perform high density sgRNA tiling screen, an sgRNA libraryagainst BAF complex subunits was custom synthesized at Cellecta(Mountain View, Calif.). Sequences of DNA encoding the BRD9-targetingsgRNAs used in this screen are listed in Table 3. Negative and positivecontrol sgRNA were included in the library. Negative controls consistedof 200 sgRNAs that do not target human genome. The positive controls aresgRNAs targeting essential genes (CDC16, GTF2B, HSPA5, HSPA9, PAFAH1B1,PCNA, POLR2L, RPL9, and SF3A3). DNA sequences encoding all positive andnegative control sgRNAs are listed in Table 4. Procedures for virusproduction, cell infection, and performing the sgRNA screen werepreviously described (Tsherniak et al, Cell 170:564-576 (2017); Munoz etal, Cancer Discovery 6:900-913 (2016)). For each sgRNA, 50 counts wereadded to the sequencing counts and for each time point the resultingcounts were normalized to the total number of counts. The log 2 of theratio between the counts (defined as dropout ratio) at day 24 and day 1post-infection was calculated. For negative control sgRNAs, the 2.5 and97.5 percentile of the log 2 dropout ratio of all non-targeting sgRNAswas calculated and considered as background (grey box in the graph).Protein domains were obtained from PFAM regions defined for the UNIPROTidentifier: Q9H8M2.

Results: As shown in FIG. 1, targeted inhibition of the GBAF complexcomponent BRD9 by sgRNA resulted in growth inhibition of the SYO1synovial sarcoma cell line. sgRNAs against other components of the BAFcomplexes resulted in increased proliferation of cells, inhibition ofcell growth, or had no effect on SYO1 cells. These data show thattargeting various subunits of the GBAF complex represents a therapeuticstrategy for the treatment of synovial sarcoma.

TABLE 3 BRD9 sgRNA Library SEQ ID NO. Nucleic Acid Sequence 203CAAGAAGCACAAGAAGCACA 204 CTTGTGCTTCTTGCCCATGG 205 CTTCTTGTGCTTCTTGCCCA206 ACAAGAAGCACAAGGCCGAG 207 CTCGTAGGACGAGCGCCACT 208CGAGTGGCGCTCGTCCTACG 209 GAGTGGCGCTCGTCCTACGA 210 AGGCTTCTCCAGGGGCTTGT211 AGATTATGCCGACAAGCCCC 212 ACCTTCAGGACTAGCTTTAG 213AGCTTTAGAGGCTTCTCCAG 214 CTAGCTTTAGAGGCTTCTCC 215 TAGCTTTAGAGGCTTCTCCA216 CTAAAGCTAGTCCTGAAGGT 217 GCCTCTAAAGCTAGTCCTGA 218CTTCACTTCCTCCGACCTTC 219 AAGCTAGTCCTGAAGGTCGG 220 AGTGAAGTGACTGAACTCTC221 GTGACTGAACTCTCAGGATC 222 ATAGTAACTGGAGTCGTGGC 223CATCATAGTAACTGGAGTCG 224 TGACCTGTCATCATAGTAAC 225 ACTCCAGTTACTATGATGAC226 CTTTGTGCCTCTCTCGCTCA 227 GGTCAGACCATGAGCGAGAG 228GAAGAAGAAGAAGTCCGAGA 229 GTCCAGATGCTTCTCCTTCT 230 GTCCGAGAAGGAGAAGCATC231 GGAGAAGCATCTGGACGATG 232 TGAGGAAAGAAGGAAGCGAA 233ATCTGGACGATGAGGAAAGA 234 AGAAGAAGCGGAAGCGAGAG 235 GAAGAAGCGGAAGCGAGAGA236 CCGCCCAGGAAGAGAAGAAG 237 AGAGAGGGAGCACTGTGACA 238AGGGAGCACTGTGACACGGA 239 GAGGGAGCACTGTGACACGG 240 GCACTGTGACACGGAGGGAG241 GAGGCTGACGACTTTGATCC 242 AGGCTGACGACTTTGATCCT 243TCCACCTCCACCTTCTTCCC 244 CGACTTTGATCCTGGGAAGA 245 CTTTGATCCTGGGAAGAAGG246 TGATCCTGGGAAGAAGGTGG 247 TCCTGGGAAGAAGGTGGAGG 248CGGACTGGCCGATCTGGGGG 249 ACGCTCGGACTGGCCGATCT 250 AGGTGGAGCCGCCCCCAGAT251 CGCTCGGACTGGCCGATCTG 252 GCTCGGACTGGCCGATCTGG 253CACGCTCGGACTGGCCGATC 254 TGTGTCCGGCACGCTCGGAC 255 CTGGCTGTGTCCGGCACGCT256 ATCGGCCAGTCCGAGCGTGC 257 CACCCTTGCCTGGCTGTGTC 258CGAGCGTGCCGGACACAGCC 259 TGTTCCAGGAGTTGCTGAAT 260 CACACCTATTCAGCAACTCC261 GCTGGCGGAGGAAGTGTTCC 262 TTTACCTCTGAAGCTGGCGG 263CCCCGGTTTACCTCTGAAGC 264 ACTTCCTCCGCCAGCTTCAG 265 CAGGAAAAGCAAAAAATCCA266 GCTTTCAGAAAAGATCCCCA 267 AGGAAAAGCAAAAAATCCAT 268GGAAAAGCAAAAAATCCATG 269 GGAGCAATTGCATCCGTGAC 270 GTCACGGATGCAATTGCTCC271 TTTATTATCATTGAATATCC 272 AATGATAATAAAACATCCCA 273ATAAAACATCCCATGGATTT 274 TTCATGGTGCCAAAATCCAT 275 TTTCATGGTGCCAAAATCCA276 TAATGAATACAAGTCAGTTA 277 CAAGTCAGTTACGGAATTTA 278ATAATGCAATGACATACAAT 279 AACTTGTAGTACACGGTATC 280 CTTCGCCAACTTGTAGTACA281 AGATACCGTGTACTACAAGT 282 GCGAAGAAGATCCTTCACGC 283TCATCTTAAAGCCTGCGTGA 284 TTCTCAGCAGGCAGCTCTTT 285 CAATGAAGATACAGCTGTTG286 ACTGGTACAACTTCAGGGAC 287 CTTGTACTGGTACAACTTCA 288ACTTGTACTGGTACAACTTC 289 TTGGCAGTTTCTACTTGTAC 290 TACCTGATAACTTCTCTACT291 AGCCGAGTAGAGAAGTTATC 292 AGCTGCATGTTTGAGCCTGA 293GCTGCATGTTTGAGCCTGAA 294 AAGCTGCAGGCATTCCCTTC 295 GGTACTGTCCGTCAAGCTGC296 AGGGAATGCCTGCAGCTTGA 297 CTTGACGGACAGTACCGCAG 298CGCCAGCACGTGCTCCTCTG 299 TACCGCAGAGGAGCACGTGC 300 AGAGGAGCACGTGCTGGCGC301 GGAGCACGTGCTGGCGCTGG 302 AGCACGCAGCTGACGAAGCT 303GCACGCAGCTGACGAAGCTC 304 CAGCTGACGAAGCTCGGGAC 305 AAGCTCGGGACAGGATCAAC306 CCTTGCCGCCTGGGAGGAAC 307 AGGATCAACCGGTTCCTCCC 308ATCAACCGGTTCCTCCCAGG 309 GCACTACCTTGCCGCCTGGG 310 AGAGCACTACCTTGCCGCCT311 CCGGTTCCTCCCAGGCGGCA 312 TCCTCTTCAGATAGCCCATC 313ATGGGCTATCTGAAGAGGAA 314 GGGCTATCTGAAGAGGAACG 315 TGGGCTATCTGAAGAGGAAC316 TATCTGAAGAGGAACGGGGA 317 ATCTGAAGAGGAACGGGGAC 318TGTTGACCACGCTGTAGAGC 319 GCTCTACAGCGTGGTCAACA 320 CGGGAGCCTGCTCTACAGCG321 CGTGGTCAACACGGCCGAGC 322 CCCACCATCAGCGTCCGGCT 323ACGGCCGAGCCGGACGCTGA 324 GGGCACCCACCATCAGCGTC 325 GCCGAGCCGGACGCTGATGG326 CCATGTCCGTGTTGCAGAGG 327 CCGAGCCGGACGCTGATGGT 328CGAGCTCAAGTCCACCGGGT 329 GCGAGCTCAAGTCCACCGGG 330 AGAGCGAGCTCAAGTCCACC331 GAGAGCGAGCTCAAGTCCAC 332 GAAGCCTGGGAGTAGCTTAC 333CTCTCCAGTAAGCTACTCCC 334 AGCCCAGCGTGGTGAAGCCT 335 AAGCCCAGCGTGGTGAAGCC336 ACTCCCAGGCTTCACCACGC 337 CTCCCAGGCTTCACCACGCT 338CTCGTCTTTGAAGCCCAGCG 339 CACTGGAGAGAAAGGTGACT 340 GCACTGGAGAGAAAGGTGAC341 AGTAGTGGCACTGGAGAGAA 342 CGAAAGCGCAGTAGTGGCAC 343CTGCATCGAAAGCGCAGTAG 344 ATGCAGAATAATTCAGTATT 345 AGTATTTGGCGACTTGAAGT346 CGACTTGAAGTCGGACGAGA 347 GAGCTGCTCTACTCAGCCTA 348CACGCCTGTCTCATCTCCGT 349 TCAGCCTACGGAGATGAGAC 350 CAGGCGTGCAGTGTGCGCTG351 CCGCGGCCCCTCTAGCCTGC 352 CATCCTTCACAAACTCCTGC 353TAGCCTGCAGGAGTTTGTGA 354 CAGGAGTTTGTGAAGGATGC 355 AGGAGTTTGTGAAGGATGCT356 TGGGAGCTACAGCAAGAAAG 357 GAGCTACAGCAAGAAAGTGG 358GAAAGTGGTGGACGACCTCC 359 CGCCTGTGATCTGGTCCAGG 360 CTCCGCCTGTGATCTGGTCC361 GACCTCCTGGACCAGATCAC 362 CTCCTGGACCAGATCACAGG 363GCTGGAAGAGCGTCCTAGAG 364 TGCAGCCCACCTGCTTCAGC 365 GACGCTCTTCCAGCTGAAGC366 CTCTTCCAGCTGAAGCAGGT 367 GCTCTTCCAGCTGAAGCAGG 368CCTCCAGATGAAGCCAAGGT 369 GCTTCATCTGGAGGCTTCAT 370 GGCTTCATCTGGAGGCTTCA371 CTTACCTTGGCTTCATCTGG 372 AAACTTACCTTGGCTTCATC 373GAAGCCTCCAGATGAAGCCA 374 TCCTAGGGTGTCCCCAACCT 375 CCTAGGGTGTCCCCAACCTG376 GTGTCTGTCTCCACAGGTTG 377 TGTGTCTGTCTCCACAGGTT 378CCACAGGTTGGGGACACCCT 379 AGAGCTGCTGCTGTCTCCTA 380 CAGAGCTGCTGCTGTCTCCT381 AGACAGCAGCAGCTCTGTTC 382 ATCCACAGAAACGTCGGGAT 383GAGATATCCACAGAAACGTC 384 GGAGATATCCACAGAAACGT 385 GTCCTATCCCGACGTTTCTG386 TCTCCATGCTCAGCTCTCTG 387 CTCACCCAGAGAGCTGAGCA 388ATCTCCATGCTCAGCTCTCT 389 TATCTCCATGCTCAGCTCTC 390 ATGTCCTGTTTACACAGGGA391 TTACACAGGGAAGGTGAAGA 392 AGTTCAAATGGCTGTCGTCA 393TGACGACAGCCATTTGAACT 394 AAGTTCAAATGGCTGTCGTC 395 TCGTCTCATCCAAGTTCAAA396 TGAGACGACGAAGCTCCTGC 397 GTGCTTCGTGCAGGTCCTGC 398GCAGGACCTGCACGAAGCAC 399 GCTCCGCCTGTGCTTCGTGC 400 GGACCTGCACGAAGCACAGG401 CACGAAGCACAGGCGGAGCG 402 AGGCGGAGCGCGGCGGCTCT 403AGGGAGCTGAGGTTGGACGA 404 GTTGGACAGGGAGCTGAGGT 405 AGGCGTTGGACAGGGAGCTG406 CCCTCTCGGAGGCGTTGGAC 407 CCTCTCGGAGGCGTTGGACA 408CTGGTCCCTCTCGGAGGCGT 409 CCCTGTCCAACGCCTCCGAG 410 CCTGTCCAACGCCTCCGAGA411 GTGGTGCTGGTCCCTCTCGG 412 CAGGTGGTGCTGGTCCCTCT 413GCATCTCACCCAGGTGGTGC 414 CGAGAGGGACCAGCACCACC 415 GAGAGGGACCAGCACCACCT416 GTGGGGGCATCTCACCCAGG 417 CCCCGACACTCAGGCGAGAA 418TCCCCGACACTCAGGCGAGA 419 AGCCCTTCTCGCCTGAGTGT 420 CTGGCTGCTCCCCGACACTC421 CCCTTCTCGCCTGAGTGTCG 422 GCCCTTCTCGCCTGAGTGTC 423TAGGGGTCGTGGGTGACGTC 424 AAGAAACTCATAGGGGTCGT 425 GAAGAAACTCATAGGGGTCG426 GAGACTGAAGAAACTCATAG 427 GGAGACTGAAGAAACTCATA 428TGGAGACTGAAGAAACTCAT 429 TCTTCAGTCTCCAGAGCCTG 430 TTGGCAGAGGCCGCAGGCTC431 TAGGTCTTGGCAGAGGCCGC 432 CTAGAGTTAGGTCTTGGCAG 433GGTGGTCTAGAGTTAGGTCT

TABLE 4 Control sgRNA Library SEQ ID Nucleic Acid NO. gRNA Label GeneSequence 434 1|sg_Non_Targeting_Human_0001| Non_Targeting_HumanGTAGCGAACGTGTCCGGCGT Non_Targeting_Human 4351|sg_Non_Targeting_Human_0002| Non_Targeting_Human GACCGGAACGATCTCGCGTANon_Targeting_Human 436 1|sg_Non_Targeting_Human_0003|Non_Targeting_Human GGCAGTCGTTCGGTTGATAT Non_Targeting_Human 4371|sg_Non_Targeting_Human_0004| Non_Targeting_Human GCTTGAGCACATACGCGAATNon_Targeting_Human 438 1|sg_Non_Targeting_Human_0005|Non_Targeting_Human GTGGTAGAATAACGTATTAC Non_Targeting_Human 4391|sg_Non_Targeting_Human_0006| Non_Targeting_Human GTCATACATGGATAAGGCTANon_Targeting_Human 440 1|sg_Non_Targeting_Human_0007|Non_Targeting_Human GATACACGAAGCATCACTAG Non_Targeting_Human 4411|sg_Non_Targeting_Human_0008| Non_Targeting_Human GAACGTTGGCACTACTTCACNon_Targeting_Human 442 1|sg_Non_Targeting_Human_0009|Non_Targeting_Human GATCCATGTAATGCGTTCGA Non_Targeting_Human 4431|sg_Non_Targeting_Human_0010| Non_Targeting_Human GTCGTGAAGTGCATTCGATCNon_Targeting_Human 444 1|sg_Non_Targeting_Human_0011|Non_Targeting_Human GTTCGACTCGCGTGACCGTA Non_Targeting_Human 4451|sg_Non_Targeting_Human_0012| Non_Targeting_Human GAATCTACCGCAGCGGTTCGNon_Targeting_Human 446 1|sg_Non_Targeting_Human_0013|Non_Targeting_Human GAAGTGACGTCGATTCGATA Non_Targeting_Human 4471|sg_Non_Targeting_Human_0014| Non_Targeting_Human GCGGTGTATGACAACCGCCGNon_Targeting_Human 448 1|sg_Non_Targeting_Human_0015|Non_Targeting_Human GTACCGCGCCTGAAGTTCGC Non_Targeting_Human 4491|sg_Non_Targeting_Human_0016| Non_Targeting_Human GCAGCTCGTGTGTCGTACTCNon_Targeting_Human 450 1|sg_Non_Targeting_Human_0017|Non_Targeting_Human GCGCCTTAAGAGTACTCATC Non_Targeting_Human 4511|sg_Non_Targeting_Human_0018| Non_Targeting_Human GAGTGTCGTCGTTGCTCCTANon_Targeting_Human 452 1|sg_Non_Targeting_Human_0019|Non_Targeting_Human GCAGCTCGACCTCAAGCCGT Non_Targeting_Human 4531|sg_Non_Targeting_Human_0020| Non_Targeting_Human GTATCCTGACCTACGCGCTGNon_Targeting_Human 454 1|sg_Non_Targeting_Human_0021|Non_Targeting_Human GTGTATCTCAGCACGCTAAC Non_Targeting_Human 4551|sg_Non_Targeting_Human_0022| Non_Targeting_Human GTCGTCATACAACGGCAACGNon_Targeting_Human 456 1|sg_Non_Targeting_Human_0023|Non_Targeting_Human GTCGTGCGCTTCCGGCGGTA Non_Targeting_Human 4571|sg_Non_Targeting_Human_0024| Non_Targeting_Human GCGGTCCTCAGTAAGCGCGTNon_Targeting_Human 458 1|sg_Non_Targeting_Human_0025|Non_Targeting_Human GCTCTGCTGCGGAAGGATTC Non_Targeting_Human 4591|sg_Non_Targeting_Human_0026| Non_Targeting_Human GCATGGAGGAGCGTCGCAGANon_Targeting_Human 460 1|sg_Non_Targeting_Human_0027|Non_Targeting_Human GTAGCGCGCGTAGGAGTGGC Non_Targeting_Human 4611|sg_Non_Targeting_Human_0028| Non_Targeting_Human GATCACCTGCATTCGTACACNon_Targeting_Human 462 1|sg_Non_Targeting_Human_0029|Non_Targeting_Human GCACACCTAGATATCGAATG Non_Targeting_Human 4631|sg_Non_Targeting_Human_0030| Non_Targeting_Human GTTGATCAACGCGCTTCGCGNon_Targeting_Human 464 1|sg_Non_Targeting_Human_0031|Non_Targeting_Human GCGTCTCACTCACTCCATCG Non_Targeting_Human 4651|sg_Non_Targeting_Human_0032| Non_Targeting_Human GCCGACCAACGTCAGCGGTANon_Targeting_Human 466 1|sg_Non_Targeting_Human_0033|Non_Targeting_Human GGATACGGTGCGTCAATCTA Non_Targeting_Human 4671|sg_Non_Targeting_Human_0034| Non_Targeting_Human GAATCCAGTGGCGGCGACAANon_Targeting_Human 468 1|sg_Non_Targeting_Human_0035|Non_Targeting_Human GCACTGTCAGTGCAACGATA Non_Targeting_Human 4691|sg_Non_Targeting_Human_0036| Non_Targeting_Human GCGATCCTCAAGTATGCTCANon_Targeting_Human 470 1|sg_Non_Targeting_Human_0037|Non_Targeting_Human GCTAATATCGACACGGCCGC Non_Targeting_Human 4711|sg_Non_Targeting_Human_0038| Non_Targeting_Human GGAGATGCATCGAAGTCGATNon_Targeting_Human 472 1|sg_Non_Targeting_Human_0039|Non_Targeting_Human GGATGCACTCCATCTCGTCT Non_Targeting_Human 4731|sg_Non_Targeting_Human_0040| Non_Targeting_Human GTGCCGAGTAATAACGCGAGNon_Targeting_Human 474 1|sg_Non_Targeting_Human_0041|Non_Targeting_Human GAGATTCCGATGTAACGTAC Non_Targeting_Human 4751|sg_Non_Targeting_Human_0042| Non_Targeting_Human GTCGTCACGAGCAGGATTGCNon_Targeting_Human 476 1|sg_Non_Targeting_Human_0043|Non_Targeting_Human GCGTTAGTCACTTAGCTCGA Non_Targeting_Human 4771|sg_Non_Targeting_Human_0044| Non_Targeting_Human GTTCACACGGTGTCGGATAGNon_Targeting_Human 478 1|sg_Non_Targeting_Human_0045|Non_Targeting_Human GGATAGGTGACCTTAGTACG Non_Targeting_Human 4791|sg_Non_Targeting_Human_0046| Non_Targeting_Human GTATGAGTCAAGCTAATGCGNon_Targeting_Human 480 1|sg_Non_Targeting_Human_0047|Non_Targeting_Human GCAACTATTGGAATACGTGA Non_Targeting_Human 4811|sg_Non_Targeting_Human_0048| Non_Targeting_Human GTTACCTTCGCTCGTCTATANon_Targeting_Human 482 1|sg_Non_Targeting_Human_0049|Non_Targeting_Human GTACCGAGCACCACAGGCCG Non_Targeting_Human 4831|sg_Non_Targeting_Human_0050| Non_Targeting_Human GTCAGCCATCGGATAGAGATNon_Targeting_Human 484 1|sg_Non_Targeting_Human_0051|Non_Targeting_Human GTACGGCACTCCTAGCCGCT Non_Targeting_Human 4851|sg_Non_Targeting_Human_0052| Non_Targeting_Human GGTCCTGTCGTATGCTTGCANon_Targeting_Human 486 1|sg_Non_Targeting_Human_0053|Non_Targeting_Human GCCGCAATATATGCGGTAAG Non_Targeting_Human 4871|sg_Non_Targeting_Human_0054| Non_Targeting_Human GCGCACGTATAATCCTGCGTNon_Targeting_Human 488 1|sg_Non_Targeting_Human_0055|Non_Targeting_Human GTGCACAACACGATCCACGA Non_Targeting_Human 4891|sg_Non_Targeting_Human_0056| Non_Targeting_Human GCACAATGTTGACGTAAGTGNon_Targeting_Human 490 1|sg_Non_Targeting_Human_0057|Non_Targeting_Human GTAAGATGCTGCTCACCGTG Non_Targeting_Human 4911|sg_Non_Targeting_Human_0058| Non_Targeting_Human GTCGGTGATCCAACGTATCGNon_Targeting_Human 492 1|sg_Non_Targeting_Human_0059|Non_Targeting_Human GAGCTAGTAGGACGCAAGAC Non_Targeting_Human 4931|sg_Non_Targeting_Human_0060| Non_Targeting_Human GTACGTGGAAGCTTGTGGCCNon_Targeting_Human 494 1|sg_Non_Targeting_Human_0061|Non_Targeting_Human GAGAACTGCCAGTTCTCGAT Non_Targeting_Human 4951|sg_Non_Targeting_Human_0062| Non_Targeting_Human GCCATTCGGCGCGGCACTTCNon_Targeting_Human 496 1|sg_Non_Targeting_Human_0063|Non_Targeting_Human GCACACGACCAATCCGCTTC Non_Targeting_Human 4971|sg_Non_Targeting_Human_0064| Non_Targeting_Human GAGGTGATCGATTAAGTACANon_Targeting_Human 498 1|sg_Non_Targeting_Human_0065|Non_Targeting_Human GTCACTCGCAGACGCCTAAC Non_Targeting_Human 4991|sg_Non_Targeting_Human_0066| Non_Targeting_Human GCGCTACGGAATCATACGTTNon_Targeting_Human 500 1|sg_Non_Targeting_Human_0067|Non_Targeting_Human GGTAGGACCTCACGGCGCGC Non_Targeting_Human 5011|sg_Non_Targeting_Human_0068| Non_Targeting_Human GAACTGCATCTTGTTGTAGTNon_Targeting_Human 502 1|sg_Non_Targeting_Human_0069|Non_Targeting_Human GATCCTGATCCGGCGGCGCG Non_Targeting_Human 5031|sg_Non_Targeting_Human_0070| Non_Targeting_Human GGTATGCGCGATCCTGAGTTNon_Targeting_Human 504 1|sg_Non_Targeting_Human_0071|Non_Targeting_Human GCGGAGCTAGAGAGCGGTCA Non_Targeting_Human 5051|sg_Non_Targeting_Human_0072| Non_Targeting_Human GAATGGCAATTACGGCTGATNon_Targeting_Human 506 1|sg_Non_Targeting_Human_0073|Non_Targeting_Human GTATGGTGAGTAGTCGCTTG Non_Targeting_Human 5071|sg_Non_Targeting_Human_0074| Non_Targeting_Human GTGTAATTGCGTCTAGTCGGNon_Targeting_Human 508 1|sg_Non_Targeting_Human_0075|Non_Targeting_Human GGTCCTGGCGAGGAGCCTTG Non_Targeting_Human 5091|sg_Non_Targeting_Human_0076| Non_Targeting_Human GAAGATAAGTCGCTGTCTCGNon_Targeting_Human 510 1|sg_Non_Targeting_Human_0077|Non_Targeting_Human GTCGGCGTTCTGTTGTGACT Non_Targeting_Human 5111|sg_Non_Targeting_Human_0078| Non_Targeting_Human GAGGCAAGCCGTTAGGTGTANon_Targeting_Human 512 1|sg_Non_Targeting_Human_0079|Non_Targeting_Human GCGGATCCAGATCTCATTCG Non_Targeting_Human 5131|sg_Non_Targeting_Human_0080| Non_Targeting_Human GGAACATAGGAGCACGTAGTNon_Targeting_Human 514 1|sg_Non_Targeting_Human_0081|Non_Targeting_Human GTCATCATTATGGCGTAAGG Non_Targeting_Human 5151|sg_Non_Targeting_Human_0082| Non_Targeting_Human GCGACTAGCGCCATGAGCGGNon_Targeting_Human 516 1|sg_Non_Targeting_Human_0083|Non_Targeting_Human GGCGAAGTTCGACATGACAC Non_Targeting_Human 5171|sg_Non_Targeting_Human_0084| Non_Targeting_Human GCTGTCGTGTGGAGGCTATGNon_Targeting_Human 518 1|sg_Non_Targeting_Human_0085|Non_Targeting_Human GCGGAGAGCATTGACCTCAT Non_Targeting_Human 5191|sg_Non_Targeting_Human_0086| Non_Targeting_Human GACTAATGGACCAAGTCAGTNon_Targeting_Human 520 1|sg_Non_Targeting_Human_0087|Non_Targeting_Human GCGGATTAGAGGTAATGCGG Non_Targeting_Human 5211|sg_Non_Targeting_Human_0088| Non_Targeting_Human GCCGACGGCAATCAGTACGCNon_Targeting_Human 522 1|sg_Non_Targeting_Human_0089|Non_Targeting_Human GTAACCTCTCGAGCGATAGA Non_Targeting_Human 5231|sg_Non_Targeting_Human_0090| Non_Targeting_Human GACTTGTATGTGGCTTACGGNon_Targeting_Human 524 1|sg_Non_Targeting_Human_0091|Non_Targeting_Human GTCACTGTGGTCGAACATGT Non_Targeting_Human 5251|sg_Non_Targeting_Human_0092| Non_Targeting_Human GTACTCCAATCCGCGATGACNon_Targeting_Human 526 1|sg_Non_Targeting_Human_0093|Non_Targeting_Human GCGTTGGCACGATGTTACGG Non_Targeting_Human 5271|sg_Non_Targeting_Human_0094| Non_Targeting_Human GAACCAGCCGGCTAGTATGANon_Targeting_Human 528 1|sg_Non_Targeting_Human_0095|Non_Targeting_Human GTATACTAGCTAACCACACG Non_Targeting_Human 5291|sg_Non_Targeting_Human_0096| Non_Targeting_Human GAATCGGAATAGTTGATTCGNon_Targeting_Human 530 1|sg_Non_Targeting_Human_0097|Non_Targeting_Human GAGCACTTGCATGAGGCGGT Non_Targeting_Human 5311|sg_Non_Targeting_Human_0098| Non_Targeting_Human GAACGGCGATGAAGCCAGCCNon_Targeting_Human 532 1|sg_Non_Targeting_Human_0099|Non_Targeting_Human GCAACCGAGATGAGAGGTTC Non_Targeting_Human 5331|sg_Non_Targeting_Human_0100| Non_Targeting_Human GCAAGATCAATATGCGTGATNon_Targeting_Human 534 1|sg_Non_Targeting_Human_GA_0101|Non_Targeting_Human ACGGAGGCTAAGCGTCGCAA Non_Targeting_Human 5351|sg_Non_Targeting_Human_GA_0102| Non_Targeting_HumanCGCTTCCGCGGCCCGTTCAA Non_Targeting_Human 5361|sg_Non_Targeting_Human_GA_0103| Non_Targeting_HumanATCGTTTCCGCTTAACGGCG Non_Targeting_Human 5371|sg_Non_Targeting_Human_GA_0104| Non_Targeting_HumanGTAGGCGCGCCGCTCTCTAC Non_Targeting_Human 5381|sg_Non_Targeting_Human_GA_0105| Non_Targeting_HumanCCATATCGGGGCGAGACATG Non_Targeting_Human 5391|sg_Non_Targeting_Human_GA_0106| Non_Targeting_HumanTACTAACGCCGCTCCTACAG Non_Targeting_Human 5401|sg_Non_Targeting_Human_GA_0107| Non_Targeting_HumanTGAGGATCATGTCGAGCGCC Non_Targeting_Human 5411|sg_Non_Targeting_Human_GA_0108| Non_Targeting_HumanGGGCCCGCATAGGATATCGC Non_Targeting_Human 5421|sg_Non_Targeting_Human_GA_0109| Non_Targeting_HumanTAGACAACCGCGGAGAATGC Non_Targeting_Human 5431|sg_Non_Targeting_Human_GA_0110| Non_Targeting_HumanACGGGCGGCTATCGCTGACT Non_Targeting_Human 5441|sg_Non_Targeting_Human_GA_0111| Non_Targeting_HumanCGCGGAAATTTTACCGACGA Non_Targeting_Human 5451|sg_Non_Targeting_Human_GA_0112| Non_Targeting_HumanCTTACAATCGTCGGTCCAAT Non_Targeting_Human 5461|sg_Non_Targeting_Human_GA_0113| Non_Targeting_HumanGCGTGCGTCCCGGGTTACCC Non_Targeting_Human 5471|sg_Non_Targeting_Human_GA_0114| Non_Targeting_HumanCGGAGTAACAAGCGGACGGA Non_Targeting_Human 5481|sg_Non_Targeting_Human_GA_0115| Non_Targeting_HumanCGAGTGTTATACGCACCGTT Non_Targeting_Human 5491|sg_Non_Targeting_Human_GA_0116| Non_Targeting_HumanCGACTAACCGGAAACTTTTT Non_Targeting_Human 5501|sg_Non_Targeting_Human_GA_0117| Non_Targeting_HumanCAACGGGTTCTCCCGGCTAC Non_Targeting_Human 5511|sg_Non_Targeting_Human_GA_0118| Non_Targeting_HumanCAGGAGTCGCCGATACGCGT Non_Targeting_Human 5521|sg_Non_Targeting_Human_GA_0119| Non_Targeting_HumanTTCACGTCGTCTCGCGACCA Non_Targeting_Human 5531|sg_Non_Targeting_Human_GA_0120| Non_Targeting_HumanGTGTCGGATTCCGCCGCTTA Non_Targeting_Human 5541|sg_Non_Targeting_Human_GA_0121| Non_Targeting_HumanCACGAACTCACACCGCGCGA Non_Targeting_Human 5551|sg_Non_Targeting_Human_GA_0122| Non_Targeting_HumanCGCTAGTACGCTCCTCTATA Non_Targeting_Human 5561|sg_Non_Targeting_Human_GA_0123| Non_Targeting_HumanTCGCGCTTGGGTTATACGCT Non_Targeting_Human 5571|sg_Non_Targeting_Human_GA_0124| Non_Targeting_HumanCTATCTCGAGTGGTAATGCG Non_Targeting_Human 5581|sg_Non_Targeting_Human_GA_0125| Non_Targeting_HumanAATCGACTCGAACTTCGTGT Non_Targeting_Human 5591|sg_Non_Targeting_Human_GA_0126| Non_Targeting_HumanCCCGATGGACTATACCGAAC Non_Targeting_Human 5601|sg_Non_Targeting_Human_GA_0127| Non_Targeting_HumanACGTTCGAGTACGACCAGCT Non_Targeting_Human 5611|sg_Non_Targeting_Human_GA_0128| Non_Targeting_HumanCGCGACGACTCAACCTAGTC Non_Targeting_Human 5621|sg_Non_Targeting_Human_GA_0129| Non_Targeting_HumanGGTCACCGATCGAGAGCTAG Non_Targeting_Human 5631|sg_Non_Targeting_Human_GA_0130| Non_Targeting_HumanCTCAACCGACCGTATGGTCA Non_Targeting_Human 5641|sg_Non_Targeting_Human_GA_0131| Non_Targeting_HumanCGTATTCGACTCTCAACGCG Non_Targeting_Human 5651|sg_Non_Targeting_Human_GA_0132| Non_Targeting_HumanCTAGCCGCCCAGATCGAGCC Non_Targeting_Human 5661|sg_Non_Targeting_Human_GA_0133| Non_Targeting_HumanGAATCGACCGACACTAATGT Non_Targeting_Human 5671|sg_Non_Targeting_Human_GA_0134| Non_Targeting_HumanACTTCAGTTCGGCGTAGTCA Non_Targeting_Human 5681|sg_Non_Targeting_Human_GA_0135| Non_Targeting_HumanGTGCGATGTCGCTTCAACGT Non_Targeting_Human 5691|sg_Non_Targeting_Human_GA_0136| Non_Targeting_HumanCGCCTAATTTCCGGATCAAT Non_Targeting_Human 5701|sg_Non_Targeting_Human_GA_0137| Non_Targeting_HumanCGTGGCCGGAACCGTCATAG Non_Targeting_Human 5711|sg_Non_Targeting_Human_GA_0138| Non_Targeting_HumanACCCTCCGAATCGTAACGGA Non_Targeting_Human 5721|sg_Non_Targeting_Human_GA_0139| Non_Targeting_HumanAAACGGTACGACAGCGTGTG Non_Targeting_Human 5731|sg_Non_Targeting_Human_GA_0140| Non_Targeting_HumanACATAGTCGACGGCTCGATT Non_Targeting_Human 5741|sg_Non_Targeting_Human_GA_0141| Non_Targeting_HumanGATGGCGCTTCAGTCGTCGG Non_Targeting_Human 5751|sg_Non_Targeting_Human_GA_0142| Non_Targeting_HumanATAATCCGGAAACGCTCGAC Non_Targeting_Human 5761|sg_Non_Targeting_Human_GA_0143| Non_Targeting_HumanCGCCGGGCTGACAATTAACG Non_Targeting_Human 5771|sg_Non_Targeting_Human_GA_0144| Non_Targeting_HumanCGTCGCCATATGCCGGTGGC Non_Targeting_Human 5781|sg_Non_Targeting_Human_GA_0145| Non_Targeting_HumanCGGGCCTATAACACCATCGA Non_Targeting_Human 5791|sg_Non_Targeting_Human_GA_0146| Non_Targeting_HumanCGCCGTTCCGAGATACTTGA Non_Targeting_Human 5801|sg_Non_Targeting_Human_GA_0147| Non_Targeting_HumanCGGGACGTCGCGAAAATGTA Non_Targeting_Human 5811|sg_Non_Targeting_Human_GA_0148| Non_Targeting_HumanTCGGCATACGGGACACACGC Non_Targeting_Human 5821|sg_Non_Targeting_Human_GA_0149| Non_Targeting_HumanAGCTCCATCGCCGCGATAAT Non_Targeting_Human 5831|sg_Non_Targeting_Human_GA_0150| Non_Targeting_HumanATCGTATCATCAGCTAGCGC Non_Targeting_Human 5841|sg_Non_Targeting_Human_GA_0151| Non_Targeting_HumanTCGATCGAGGTTGCATTCGG Non_Targeting_Human 5851|sg_Non_Targeting_Human_GA_0152| Non_Targeting_HumanCTCGACAGTTCGTCCCGAGC Non_Targeting_Human 5861|sg_Non_Targeting_Human_GA_0153| Non_Targeting_HumanCGGTAGTATTAATCGCTGAC Non_Targeting_Human 5871|sg_Non_Targeting_Human_GA_0154| Non_Targeting_HumanTGAACGCGTGTTTCCTTGCA Non_Targeting_Human 5881|sg_Non_Targeting_Human_GA_0155| Non_Targeting_HumanCGACGCTAGGTAACGTAGAG Non_Targeting_Human 5891|sg_Non_Targeting_Human_GA_0156| Non_Targeting_HumanCATTGTTGAGCGGGCGCGCT Non_Targeting_Human 5901|sg_Non_Targeting_Human_GA_0157| Non_Targeting_HumanCCGCTATTGAAACCGCCCAC Non_Targeting_Human 5911|sg_Non_Targeting_Human_GA_0158| Non_Targeting_HumanAGACACGTCACCGGTCAAAA Non_Targeting_Human 5921|sg_Non_Targeting_Human_GA_0159| Non_Targeting_HumanTTTACGATCTAGCGGCGTAG Non_Targeting_Human 5931|sg_Non_Targeting_Human_GA_0160| Non_Targeting_HumanTTCGCACGATTGCACCTTGG Non_Targeting_Human 5941|sg_Non_Targeting_Human_GA_0161| Non_Targeting_HumanGGTTAGAGACTAGGCGCGCG Non_Targeting_Human 5951|sg_Non_Targeting_Human_GA_0162| Non_Targeting_HumanCCTCCGTGCTAACGCGGACG Non_Targeting_Human 5961|sg_Non_Targeting_Human_GA_0163| Non_Targeting_HumanTTATCGCGTAGTGCTGACGT Non_Targeting_Human 5971|sg_Non_Targeting_Human_GA_0164| Non_Targeting_HumanTACGCTTGCGTTTAGCGTCC Non_Targeting_Human 5981|sg_Non_Targeting_Human_GA_0165| Non_Targeting_HumanCGCGGCCCACGCGTCATCGC Non_Targeting_Human 5991|sg_Non_Targeting_Human_GA_0166| Non_Targeting_HumanAGCTCGCCATGTCGGTTCTC Non_Targeting_Human 6001|sg_Non_Targeting_Human_GA_0167| Non_Targeting_HumanAACTAGCCCGAGCAGCTTCG Non_Targeting_Human 6011|sg_Non_Targeting_Human_GA_0168| Non_Targeting_HumanCGCAAGGTGTCGGTAACCCT Non_Targeting_Human 6021|sg_Non_Targeting_Human_GA_0169| Non_Targeting_HumanCTTCGACGCCATCGTGCTCA Non_Targeting_Human 6031|sg_Non_Targeting_Human_GA_0170| Non_Targeting_HumanTCCTGGATACCGCGTGGTTA Non_Targeting_Human 6041|sg_Non_Targeting_Human_GA_0171| Non_Targeting_HumanATAGCCGCCGCTCATTACTT Non_Targeting_Human 6051|sg_Non_Targeting_Human_GA_0172| Non_Targeting_HumanGTCGTCCGGGATTACAAAAT Non_Targeting_Human 6061|sg_Non_Targeting_Human_GA_0173| Non_Targeting_HumanTAATGCTGCACACGCCGAAT Non_Targeting_Human 6071|sg_Non_Targeting_Human_GA_0174| Non_Targeting_HumanTATCGCTTCCGATTAGTCCG Non_Targeting_Human 6081|sg_Non_Targeting_Human_GA_0175| Non_Targeting_HumanGTACCATACCGCGTACCCTT Non_Targeting_Human 6091|sg_Non_Targeting_Human_GA_0176| Non_Targeting_HumanTAAGATCCGCGGGTGGCAAC Non_Targeting_Human 6101|sg_Non_Targeting_Human_GA_0177| Non_Targeting_HumanGTAGACGTCGTGAGCTTCAC Non_Targeting_Human 6111|sg_Non_Targeting_Human_GA_0178| Non_Targeting_HumanTCGCGGACATAGGGCTCTAA Non_Targeting_Human 6121|sg_Non_Targeting_Human_GA_0179| Non_Targeting_HumanAGCGCAGATAGCGCGTATCA Non_Targeting_Human 6131|sg_Non_Targeting_Human_GA_0180| Non_Targeting_HumanGTTCGCTTCGTAACGAGGAA Non_Targeting_Human 6141|sg_Non_Targeting_Human_GA_0181| Non_Targeting_HumanGACCCCCGATAACTTTTGAC Non_Targeting_Human 6151|sg_Non_Targeting_Human_GA_0182| Non_Targeting_HumanACGTCCATACTGTCGGCTAC Non_Targeting_Human 6161|sg_Non_Targeting_Human_GA_0183| Non_Targeting_HumanGTACCATTGCCGGCTCCCTA Non_Targeting_Human 6171|sg_Non_Targeting_Human_GA_0184| Non_Targeting_HumanTGGTTCCGTAGGTCGGTATA Non_Targeting_Human 6181|sg_Non_Targeting_Human_GA_0185| Non_Targeting_HumanTCTGGCTTGACACGACCGTT Non_Targeting_Human 6191|sg_Non_Targeting_Human_GA_0186| Non_Targeting_HumanCGCTAGGTCCGGTAAGTGCG Non_Targeting_Human 6201|sg_Non_Targeting_Human_GA_0187| Non_Targeting_HumanAGCACGTAATGTCCGTGGAT Non_Targeting_Human 6211|sg_Non_Targeting_Human_GA_0188| Non_Targeting_HumanAAGGCGCGCGAATGTGGCAG Non_Targeting_Human 6221|sg_Non_Targeting_Human_GA_0189| Non_Targeting_HumanACTGCGGAGCGCCCAATATC Non_Targeting_Human 6231|sg_Non_Targeting_Human_GA_0190| Non_Targeting_HumanCGTCGAGTGCTCGAACTCCA Non_Targeting_Human 6241|sg_Non_Targeting_Human_GA_0191| Non_Targeting_HumanTCGCAGCGGCGTGGGATCGG Non_Targeting_Human 6251|sg_Non_Targeting_Human_GA_0192| Non_Targeting_HumanATCTGTCCTAATTCGGATCG Non_Targeting_Human 6261|sg_Non_Targeting_Human_GA_0193| Non_Targeting_HumanTGCGGCGTAATGCTTGAAAG Non_Targeting_Human 6271|sg_Non_Targeting_Human_GA_0194| Non_Targeting_HumanCGAACTTAATCCCGTGGCAA Non_Targeting_Human 6281|sg_Non_Targeting_Human_GA_0195| Non_Targeting_HumanGCCGTGTTGCTGGATACGCC Non_Targeting_Human 6291|sg_Non_Targeting_Human_GA_0196| Non_Targeting_HumanTACCCTCCGGATACGGACTG Non_Targeting_Human 6301|sg_Non_Targeting_Human_GA_0197| Non_Targeting_HumanCCGTTGGACTATGGCGGGTC Non_Targeting_Human 6311|sg_Non_Targeting_Human_GA_0198| Non_Targeting_HumanGTACGGGGCGATCATCCACA Non_Targeting_Human 6321|sg_Non_Targeting_Human_GA_0199| Non_Targeting_HumanAAGAGTAGTAGACGCCCGGG Non_Targeting_Human 6331|sg_Non_Targeting_Human_GA_0200| Non_Targeting_HumanAAGAGCGAATCGATTTCGTG Non_Targeting_Human 634 3|sg_hCDC16_CC_1|CDC16CDC16 TCAACACCAGTGCCTGACGG 635 3|sg_hCDC16_CC_2|CDC16 CDC16AAAGTAGCTTCACTCTCTCG 636 3|sg_hCDC16_CC_3|CDC16 CDC16GAGCCAACCAATAGATGTCC 637 3|sg_hCDC16_CC_4|CDC16 CDC16GCGCCGCCATGAACCTAGAG 638 3|sg_hGTF2B_CC_1|GTF2B GTF2BACAAAGGTTGGAACAGAACC 639 3|sg_hGTF2B_CC_2|GTF2B GTF2BGGTGACCGGGTTATTGATGT 640 3|sg_hGTF2B_CC_3|GTF2B GTF2BTTAGTGGAGGACTACAGAGC 641 3|sg_hGTF2B_CC_4|GTF2B GTF2BACATATAGCCCGTAAAGCTG 642 3|sg_hHSPA5_CC_1|HSPA5 HSPA5CGTTGGCGATGATCTCCACG 643 3|sg_hHSPA5_CC_2|HSPA5 HSPA5TGGCCTTTTCTACCTCGCGC 644 3|sg_hHSPA5_CC_3|HSPA5 HSPA5AATGGAGATACTCATCTGGG 645 3|sg_hHSPA5_CC_4|HSPA5 HSPA5GAAGCCCGTCCAGAAAGTGT 646 3|sg_hHSPA9_CC_1|HSPA9 HSPA9CAATCTGAGGAACTCCACGA 647 3|sg_hHSPA9_CC_2|HSPA9 HSPA9AGGCTGCGGCGCCCACGAGA 648 3|sg_hHSPA9_CC_3|HSPA9 HSPA9ACTTTGACCAGGCCTTGCTA 649 3|sg_hHSPA9_CC_4|HSPA9 HSPA9ACCTTCCATAACTGCCACGC 650 3|sg_hPAFAH1B1_CC_1|PAFAH1B1 PAFAH1B1CGAGGCGTACATACCCAAGG 651 3|sg_hPAFAH1B1_CC_2|PAFAH1B1 PAFAH1B1ATGGTACGGCCAAATCAAGA 652 3|sg_hPAFAH1B1_CC_3|PAFAH1B1 PAFAH1B1TCTTGTAATCCCATACGCGT 653 3|sg_hPAFAH1B1_CC_4|PAFAH1B1 PAFAH1B1ATTCACAGGACACAGAGAAT 654 3|sg_hPCNA_CC_1|PCNA PCNA CCAGGGCTCCATCCTCAAGA655 3|sg_hPCNA_CC_2|PCNA PCNA TGAGCTGCACCAAAGAGACG 6563|sg_hPCNA_CC_3|PCNA PCNA ATGTCTGCAGATGTACCCCT 657 3|sg_hPCNA_CC_4|PCNAPCNA CGAAGATAACGCGGATACCT 658 3|sg_hPOLR2L_CC_1|POLR2L POLR2LGCTGCAGGCCGAGTACACCG 659 3|sg_hPOLR2L_CC_2|POLR2L POLR2LACAAGTGGGAGGCTTACCTG 660 3|sg_hPOLR2L_CC_3|POLR2L POLR2LGCAGCGTACAGGGATGATCA 661 3|sg_hPOLR2L_CC_4|POLR2L POLR2LGCAGTAGCGCTTCAGGCCCA 662 3|sg_hRPL9_CC_1|RPL9 RPL9 CAAATGGTGGGGTAACAGAA663 3|sg_hRPL9_CC_2|RPL9 RPL9 GAAAGGAACTGGCTACCGTT 6643|sg_hRPL9_CC_3|RPL9 RPL9 AGGGCTTCCGTTACAAGATG 665 3|sg_hRPL9_CC_4|RPL9RPL9 GAACAAGCAACACCTAAAAG 666 3|sg_hSF3A3_CC_1|SF3A3 SF3A3TGAGGAGAAGGAACGGCTCA 667 3|sg_hSF3A3_CC_2|SF3A3 SF3A3GGAAGAATGCAGAGTATAAG 668 3|sg_hSF3A3_CC_3|SF3A3 SF3A3GGAATTTGAGGAACTCCTGA 669 3|sg_hSF3A3_CC_4|SF3A3 SF3A3GCTCACCGGCCATCCAGGAA 670 3|sg_hSF3B3_CC_1|SF3B3 SF3B3ACTGGCCAGGAACGATGCGA 671 3|sg_hSF3B3_CC_2|SF3B3 SF3B3GCAGCTCCAAGATCTTCCCA 672 3|sg_hSF3B3_CC_3|SF3B3 SF3B3GAATGAGTACACAGAACGGA 673 3|sg_hSF3B3_CC_4|SF3B3 SF3B3GGAGCAGGACAAGGTCGGGG

Example 2—BRD9 Degrader Depletes BRD9 Protein

The following example demonstrates the depletion of the BRD9 protein insynovial sarcoma cells treated with a BRD9 degrader.

Procedure: Cells were treated with DMSO or the BRD9 degrader, Compound 1(also known as dBRD9, see Remillard et al, Angew. Chem. Int. Ed. Engl.56(21):5738-5743 (2017); see structure of compound 1 below), forindicated doses and timepoints.

Whole cell extracts were fractionated by SDS-PAGE and transferred to apolyvinylidene difluoride membrane using a transfer apparatus accordingto the manufacturer's protocols (Bio-Rad). After incubation with 5%nonfat milk in TBST (10 mM Tris, pH 8.0, 150 mM NaCl, 0.5% Tween 20) for60 min, the membrane was incubated with antibodies against BRD9(1:1,000, Bethyl laboratory A303-781A), GAPDH (1:5,000, Cell SignalingTechnology), and/or MBP (1:1,000, BioRad) overnight at 4° C. Membraneswere washed three times for 10 min and incubated with anti-mouse oranti-rabbit antibodies conjugated with either horseradish peroxidase(HRP, FIGS. 2-3) or IRDye (FIG. 4, 1:20,000, LI-COR) for at least 1 h.Blots were washed with TBST three times and developed with either theECL system according to the manufacturer's protocols (FIGS. 2-3) orscanned on an Odyssey CLx Imaging system (FIG. 4).

Results: Treatment of SYO1 synovial sarcoma cells with the BRD9 degraderCompound 1 results in dose dependent (FIG. 2) and time dependent (FIG.3) depletion of BRD9 in the cells. Further, as shown in FIG. 4, thedepletion of BRD9 by Compound 1 is replicated in a non-synovial sarcomacell line (293T) and may be sustained for at least 5 days.

Example 3—Inhibition of Growth of Synovial Cell Lines by BRD9 Inhibitorsand BRD9 Degraders

The following example demonstrates that BRD9 degraders and inhibitorsselectively inhibit growth of synovial sarcoma cells.

Procedures:

Cells were treated with DMSO or the BRD9 degrader, Compound 1, atindicated concentrations, and proliferation was monitored from day 7 today 14 by measuring confluency over time using an IncuCyte live cellanalysis system (FIG. 5). Growth medium and compounds were refreshedevery 3-4 days.

Cells were seeded into 12-well plates and treated with DMSO, 1 μM BRD9inhibitor, Compound 2 (also known as BI-7273, see Martin et al, J MedChem. 59(10):4462-4475 (2016); see structure of compound 2 below), or 1μM BRD9 degrader, Compound 1.

The number of cells was optimized for each cell line. Growth medium andcompounds were refreshed every 3-5 days. SYO1, Yamato, A549, 293T andHS-SY-II cells were fixed and stained at day 11. ASKA cells were fixedand stained at day 23. Staining was done by incubation with crystalviolet solution (0.5 g Crystal Violet, 27 ml 37% Formaldehyde, 100 mL10×PBS, 10 mL Methanol, 863 dH20 to 1 L) for 30 min followed by 3×washes with water and drying the plates for at least 24 h at roomtemperature. Subsequently plates were scanned on an Odyssey CLx Imagingsystem (FIG. 6).

Cells were seeded into 96-well ultra low cluster plate (Costar, #7007)in 200 μL complete media and treated at day 2 with DMSO, Staurosporin,or BRD9 degarder, Compound 1, at indicated doses (FIG. 3C). Media andcompounds were changed every 5 d and cell colonies were imaged at day14.

Results: As shown in FIGS. 5, 6, and 7, treatment of synovial sarcomacell lines (SYO1, Yamato, HS-SY-II, and ASKA) with a BRD9 inhibitor,Compound 2, or a BRD9 degrader, Compound 1, results in inhibition of thegrowth of the cells, but does not result in inhibition of the growth ofnon-synovial control cancer cell lines (293T, A549, G401).

Example 4—Selective Inhibition of Growth of Synovial Cell Lines by BRD9Degraders and BRD9 Binders

The following example demonstrates that BRD9 degraders and bindersselectively inhibit growth of synovial sarcoma cells.

Procedure: Cells were seeded into 6-well or 12-well plates and weretreated daily with a BRD9 degrader (Compound 1), a bromo-domain BRD9binder (Compound 2), E3 ligase binder (lenalidomide), DMSO, orstaurosporin (positive control for cell killing), at indicatedconcentrations. The number of cells was optimized for each cell line.Growth media was refreshed every 5 days. By day 14, medium was removed,cells were washed with PBS, and stained using 500 μL of 0.005% (w/v)crystal violet solution in 25% (v/v) methanol for at least 1 hour atroom temperature. Subsequently plates were scanned on an Odyssey CLxImaging system.

Results: As shown in FIGS. 8 and 9, treatment of synovial sarcoma celllines (SYO1, HS-SY-II, and ASKA) with Compound 1 or Compound 2 resultedin inhibition of the growth of the cells, but did not result ininhibition of the growth of non-synovial control cancer cell lines (RD,HCT116, and Calu6). Overall, Compound 1 showed most significant growthinhibition in all synovial cell lines.

Example 5—Inhibition of Cell Growth in Synovial Sarcoma Cells

The following example shows that BRD9 degraders inhibit cell growth andinduce apoptosis in synovial sarcoma cells.

Procedure: SYO1 cells were treated for 8 or 13 days with DMSO, a BRD9degrader (Compound 1) at 200 nM or 1 μM, or an E3 ligase binder(lenalidomide) at 200 nM. Compounds were refreshed every 5 days. Cellcycle analysis was performed using the Click-iT™ Plus EdU Flow CytometryAssay (Invitrogen). The apoptosis assay was performed using the AnnexinV-FITC Apoptosis Detection Kit (Sigma A9210). Assays were performedaccording to the manufacturer's protocol.

Results: As shown in FIGS. 10-13, treatment with Compound 1 for 8 or 13days resulted in reduced numbers of cells in the S-phase of the cellcycle as compared to DMSO and lenalidomide. Treatment with Compound 1for 8 days also resulted in increased numbers of early- andlate-apoptotic cells as compared to DMSO controls.

Example 6—Composition for SS18-SSX1-BAF

The following example shows the identification of BRD9 as a component ofSS18-SSX containing BAF complexes.

Procedure: A stable 293T cell line expressing HA-SS18SSX1 was generatedusing lentiviral integration. SS18-SSX1 containing BAF complexes weresubject to affinity purification and subsequent mass spectrometryanalysis revealed SS18-SSX1 interacting proteins.

Results: As shown in FIG. 14, BAF complexes including the SS18-SSXfusion protein also included BRD9. More than 5 unique peptides wereidentified for ARID1A (95 peptides), ARID1B (77 peptides), SMARCC1 (69peptides), SMARCD1 (41 peptides), SMARCD2 (37 peptides), DPF2 (32peptides), SMARCD3 (26 peptides), ACTL6A (25 peptides), BRD9 (22peptides), DPF1 Isoform 2 (18 peptides), DPF3 (13 peptides), and ACTL6B(6 peptides).

Example 7—Preparation of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2,9-dimethyl-5H,6H,10H,11H,11aH-pyrimido[4,3-a] 2,7-naphthyridine-1,8-dione (Compound B1)

Step 1: Preparation of6-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-amine (i-2)

A solution of 2-chloro-4-methylpyridine-3-carbonitrile (3.00 g, 19.662mmol, 1.00 equiv) in DMF-DMA (120.00 mL, 896.257 mmol, 45.58 equiv) wasstirred for 6 hours at 110° C. The resulting mixture was concentrated.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 3.4 g (83.27%) of2-chloro-4-[(E)-2-(dimethylamino)ethenyl]pyridine-3-carbonitrile as alight yellow solid. LCMS (ESI) m/z: [M+H]+=208.

Step 2: Preparation of 8-chloro-1,2-dihydro-2,7-naphthyridin-1-one (i-3)

Into a 250-mL round-bottom flask, was placed2-chloro-4-[(E)-2-(dimethylamino)ethenyl]pyridine-3-carbonitrile (3.40g, 16.373 mmol, 1.00 equiv), H₂SO₄ (100.00 mL). The resulting solutionwas stirred for 2 hours at 110° C. The reaction was then quenched by theaddition of 100 mL of water/ice. The pH of the solution was adjusted topH>7 by addition of aqueous (aq.) K₂CO₃. The resulting solution wasextracted with ethyl acetate (3×300 mL) and the organic layers combinedand concentrated. This resulted in 2.7 g (91.32%) of8-chloro-1,2-dihydro-2,7-naphthyridin-1-one as a light yellow solid.LCMS (ESI) m/z: [M+H]+=181.

Step 3: Preparation of 8-chloro-1,2-dihydro-2,7-naphthyridin-1-one (i-4)

To a solution of 8-chloro-1,2-dihydro-2,7-naphthyridin-1-one (2.20 g,12.182 mmol, 1.00 equiv) in THE (120.00 mL) was added NaH (321.00 mg,13.376 mmol, 1.10 equiv) and Mel (3.45 g, 24.306 mmol, 2.00 equiv). Theresulting solution was stirred for 2 hours at room temperature. Thereaction was then quenched by the addition of 100 mL of water andextracted with ethyl acetate (3×250 mL), and the organic layers werecombined and concentrated. This resulted in 2 g (84.36%) of8-chloro-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one as a light yellowsolid. LCMS (ESI) m/z: [M+H]+=195.

Step 4: Preparation of8-ethenyl-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one (i-5)

To a solution of 8-chloro-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(2.0 g, 10.276 mmol, 1.00 equiv) in 1,4-dioxane (72.00 mL) and H₂O(24.00 mL), was added Cs₂CO₃ (10.0 g, 30.727 mmol, 2.99 equiv) and2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.2 g, 20.758 mmol,2.02 equiv), Pd(dppf)Cl₂.CH₂Cl₂ (1.68 g, 2.055 mmol, 0.20 equiv) at 25°C. The resulting solution was stirred for 2 hours at 80° C. Theresulting mixture was concentrated. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 980 mg (51.21%) of8-ethenyl-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one as a light yellowsolid. LCMS (ESI) m/z: [M+H]+=187.

Step 5: Preparation of2-methyl-8-[2-(methylamino)ethyl]-1,2-dihydro-2,7-naphthyridin-1-one(i-6)

To a solution of 8-ethenyl-2-methyl-1, 2-dihydro-2, 7-naphthyridin-1-one(580 mg, 2.67 mmol, 1.00 equiv) in THE (2.00 mL) was added 4 M MeNH₂ THFsolution (20 mL) dropwise at 25° C. The resulting solution was stirredfor 5 hours at 90° C. The reaction was cooled and concentrated, thecrude product was purified by Flash-Prep-HPLC (Conditions(IntelFlash-1): Column, C18 silica gel; mobile phase, acetonitrile (MeCNor ACN) in water, 10% to 50% gradient in 10 minutes; detector, UV 254nm). This resulted in 480 mg (71.0%) of 2-methyl-8-[2-(methylamino)ethyl]-1, 2-dihydro-2, 7-naphthyridin-1-one as light yellow oil. LCMS(ESI) m/z: [M+H]+=218.

Step 6: Preparation of2-methyl-8-[2-(methylamino)ethyl]-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(i-7)

To a solution of2-methyl-8-[2-(methylamino)ethyl]-1,2-dihydro-2,7-naphthyridin-1-one(480.00 mg, 2.201 mmol, 1.00 equiv) in MeOH (10.00 mL) was added PtO₂(386.71 mg, 1.703 mmol, 0.74 equiv) under high pressure of H2 (22.0 atm)atmosphere at 25° C. The resulting solution was stirred for 12 hours atroom temperature. The solids were filtered out. The filtrate wasconcentrated. This resulted in 350 mg crude of2-methyl-8-[2-(methylamino)ethyl]-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-oneas light yellow oil, that was used directly without furtherpurification. LCMS (ESI) m/z: [M+H]+=222.

Step 7: Preparation of2,9-dimethyl-1H,2H,5H,6H,8H,9H,10H,11H,11aH-pyrimido[4,3-a]2,7-naphthyridine-1,8-dione(i-8)

To a solution of2-methyl-8-[2-(methylamino)ethyl]-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(350.00 mg, 1.576 mmol, 1.00 equiv) in THE (3.00 mL) was added CDI(1,1′-carbonyldiimidazole) (511.0 mg, 3.153 mmol, 2.00 equiv) at roomtemperature. The resulting solution was stirred for 6 hours at 70° C.The mixture was concentrated. This resulted in 340 mg crude of2,9-dimethyl-1H,2H,5H,6H,8H,9H,10H,11H,11aH-pyrimido[4,3-a]2,7-naphthyridine-1,8-dione as light yellow oil, thatwas used directly without further purification. LCMS (ESI) m/z:[M+H]+=248.

Step 8: Preparation of4-bromo-2,9-dimethyl-1H,2H,5H,6H,8H,9H,10H,11H,11aH-pyrimido[4,3-a]2,7-naphthyridine-1,8-dione(i-9)

To a solution of 2,9-dimethyl-1H,2H,5H,6H,8H,9H,1 OH, 11H,11aH-pyrimido[4,3-a]2,7-naphthyridine-1,8-dione (340.00 mg, 1.371 mmol,1.00 equiv) in HOAc (20.00 mL) was added NBS (732.1 mg, 4.113 mmol, 2.99equiv) at room temperature. The resulting solution was stirred for 12hours at room temperature. The mixture was concentrated. The crudeproduct was purified by Flash-Prep-HPLC (conditions (IntelFlash-1):Column, C18 silica gel; mobile phase, MeCN/H₂O=0 increasing toMeCN/H₂O=100 within 30 minutes; Detector, 254 nm. This resulted in 385mg of 4-bromo-2,9-dimethyl-1H,2H,5H,6H,8H,9H,10H,11H,11aH-pyrimido[4,3-a]2,7-naphthyridine-1,8-dione as a light yellow solid.LCMS (ESI) m/z: [M+H]+=326.

Step 9: Preparation of4-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-2,9-dimethyl-5,6,9,10,11,11a-hexahydro-1H-pyrimido[6,1-a][2,7]naphthyridine-1,8(2H)-dione(Compound B1)

To a solution of 4-bromo-2,9-dimethyl-5H,6H,10H,11H,11aH-pyrimido[4,3-a]2,7-naphthyridine-1,8-dione (110.00 mg, 0.337 mmol,1.00 equiv) in Dioxane (4.00 mL) and H₂O (1.00 mL) was added4-[(dimethylamino)methyl]-3,5-dimethoxyphenylboronic acid (161.25 mg,0.674 mmol, 2.00 equiv), Cs₂CO₃ (329.62 mg, 1.012 mmol, 3.00 equiv) andPd(dppf)Cl₂ (49.35 mg, 0.067 mmol, 0.20 equiv) at 25° C. The resultingsolution was stirred for 12 hours at 80° C. The solids were filteredout. The filtrate was concentrated. The crude product was purified byPrep-HPLC with the following conditions: Column, SunFire Prep C18 OBDColumn, 19, 150 mm 5 μm 10 nm; mobile phase, Water (0.1% FA) and ACN (3%Phase B up to 10% in 35 minutes); Detector, UV. This resulted in 12 mg(7.31%) of 4-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-2,9-dimethyl-5,6,9,10,11,11a-hexahydro-1H-pyrimido[6,1-a][2,7]naphthyridine-1,8(2H)-dioneformate as a light yellow semi-solid. ¹H NMR (300 MHz, Methanol-d4) δ8.51 (s, 1.35H, FA), 7.66 (s, 1H), 6.74 (s, 2H), 4.75-4.46 (m, 2H), 4.38(s, 2H), 3.96 (s, 6H), 3.64 (s, 3H), 3.61-3.50 (m, 1H), 3.29 (dd, J=5.3,1.8 Hz, 1H), 2.99 (s, 4H), 2.89 (s, 6H), 2.85-2.73 (m, 1H), 2.70-2.54(m, 1H), 2.39 (d, J=16.7 Hz, 1H), 1.73-1.49 (m, 1H). LCMS (ESI) m/z:[M+H]+=441.30.

Example 8—Preparation8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxylicacid (Compound B2)

Step 1: Preparation of 5-bromo-2-chloro-N-methylpyridine-4-carboxamide(i-11)

To a solution of 5-bromo-2-chloropyridine-4-carboxylic acid (10 g,42.292 mmol, 1 equiv) and methanamine (1.58 g, 50.751 mmol, 1.2 equiv)in solvent DCM (100 mL) was added HATU (24.12 g, 63.438 mmol, 1.5 equiv)and DIEA (27.33 g, 211.461 mmol, 5 equiv), The resulting solution wasstirred at 25° C. for 2 hours. The resulting mixture was diluted withH₂O (50 mL) and extracted with DCM (3×50 ml). The organic layers weredried over anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE/EA (5:1) to afford5-bromo-2-chloro-N-methylpyridine-4-carboxamide (8.3 g, 78.66%) as awhite solid. LCMS (ESI) m/z: [M+H]+=248.9, 250.9.

Step 2: Preparation of2-chloro-5-[(E)-2-ethoxyethenyl]-N-methylpyridine-4-carboxamide (i-12)

To a solution of 5-bromo-2-chloro-N-methylpyridine-4-carboxamide (8.00g, 32.065 mmol, 1.00 equiv) and2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.35 g,32.065 mmol, 1.0 equiv) in dioxane (50.00 mL) and H₂O (5.00 mL) wasadded Pd(dppf)Cl₂ (2.35 g, 3.207 mmol, 0.1 equiv) and Cs₂CO₃ (20.90 g,64.131 mmol, 2.0 equiv). The resulting solution was stirred at 90° C.for 2 hours under N₂ atmosphere. The resulting mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE/EA (4:1) to afford2-chloro-5-[(E)-2-ethoxyethenyl]-N-methylpyridine-4-carboxamide (5.4 g,69.97%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=241.1.

Step 3: Preparation of7-chloro-2-methyl-1,2-dihydro-2,6-naphthyridin-1-one (i-13)

To a solution of2-chloro-5-[(E)-2-ethoxyethenyl]-N-methylpyridine-4-carboxamide (5.40 g,22.435 mmol, 1.00 equiv) in solvent TFA (20.00 mL) was refluxed at 100°C. for 3 hours. The mixture was basified with sodium bicarbonatesaturated solution to pH 9. The resulting mixture was extracted with DCM(3×30 mL). The combined organic layers were washed with saturated sodiumchloride solution and dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withPE/EA (5:1) to afford7-chloro-2-methyl-1,2-dihydro-2,6-naphthyridin-1-one (3.2 g, 73.29%) asa yellow solid. LCMS (ESI) m/z: [M+H]+=195.0.

Step 4: Preparation of methyl6-methyl-5-oxo-5,6-dihydro-2,6-naphthyridine-3-carboxylate (i-14)

To a solution of 7-chloro-2-methyl-1,2-dihydro-2,6-naphthyridin-1-one(3.20 g, 16.442 mmol, 1.00 equiv) and Pd(dppf)Cl₂ (2.41 g, 3.288 mmol,0.2 equiv) in MeOH (30.00 mL) and TEA (5 mL) was refluxed at 100° C. for15 hours under 20 atm CO atmosphere. The resulting mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with PE/EA (4:1) to afford methyl6-methyl-5-oxo-5,6-dihydro-2,6-naphthyridine-3-carboxylate (1.8 g,50.17%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=219.1.

Step 5: Preparation of methyl6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxylate(i-15)

A solution of methyl6-methyl-5-oxo-5,6-dihydro-2,6-naphthyridine-3-carboxylate (1.80 g,8.249 mmol, 1.00 equiv) and PtO₂ (0.94 g, 0.004 mmol, 0.5 equiv) in EtOH(20 mL) was stirred at 25° C. for 15 hours under 20 atm H₂ atmosphere.The resulting mixture was concentrated under reduced pressure thenpurified by silica gel column chromatography, eluted with DCM/MeOH(10/1) to afford methyl6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxylate(960 mg, 52.37%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=223.1.

Step 6: Preparation of 2-tert-butyl 3-methyl6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-2,3-dicarboxylate(i-16)

A solution of methyl6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxylate(900.00 mg, 4.050 mmol, 1.00 equiv) and (Boc)₂O (2.65 g, 12.149 mmol,3.0 equiv) in DCM (30.00 mL) was stirred at 25° C. for 1 hour. Theresulting mixture was concentrated under reduced pressure then purifiedby silica gel column chromatography, eluted with PE/EA (5/1) to afford2-tert-butyl 3-methyl6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-2,3-dicarboxylate(760 mg, 58.22%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=323.2.

Step 7: Preparation of 2-tert-butyl 3-methyl8-bromo-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-2,3-dicarboxylate(i-17)

A solution of 2-tert-butyl 3-methyl6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-2,3-dicarboxylate(760.00 mg, 2.358 mmol, 1.00 equiv) and NBS (503.54 mg, 2.829 mmol, 1.20equiv) in DCM (10.00 mL) was stirred at 25° C. for 2 hours. Theresulting mixture was extracted with DCM (20 mL×3). The combined organiclayers were washed with H₂O and then dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure and purified by silica gel column chromatography, eluted withPE/EA (4/1) to afford 2-tert-butyl 3-methyl8-bromo-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-2,3-dicarboxylate(680 mg, 71.88%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=401.1, 403.1.

Step 8: Preparation of 2-tert-butyl 3-methyl8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-2,3-dicarboxylate(i-18)

To a solution of 2-tert-butyl 3-methyl8-bromo-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-2,3-dicarboxylate(680.00 mg, 1.695 mmol, 1.00 equiv) and[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl] boronic acid (607.74 mg,2.542 mmol, 1.50 equiv) in dioxane (10.00 mL) and H₂O (2.00 mL) wasadded Pd(dppf)Cl₂ (248.00 mg, 0.339 mmol, 0.20 equiv) and Cs₂CO₃(1656.48 mg, 5.084 mmol, 3.00 equiv). The resulting solution was stirredat 90° C. for 2 hours. The resulting mixture was concentrated underreduced pressure then purified by silica gel column chromatography,eluted with DCM/MeOH (10/1) to afford 2-tert-butyl 3-methyl8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-2,3-dicarboxylate(480 mg, 54.93%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=516.3.

Step 9: Preparation of2-[(tert-butoxy)carbonyl]-8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxylicacid (i-19)

A solution of 2-tert-butyl 3-methyl8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-2,3-dicarboxylate(480.00 mg, 0.931 mmol, 1.00 equiv) and LiOH (44.59 mg, 1.862 mmol, 2.00equiv) in solvent EtOH (20.00 mL) was stirred at 25° C. for 2 hours. Theresidue was purified by reverse flash chromatography with the followingconditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to20% gradient in 8 minutes; detector, UV 254 nm to afford2-[(tert-butoxy)carbonyl]-8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxylic acid (210 mg, 44.97%) as ayellow solid. LCMS (ESI) m/z: [M+H]+=502.2.

Step 10: Preparation of8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxylicacid (Compound B2)

2-[(tert-butoxy)carbonyl]-8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxylicacid (30.00 mg, 0.060 mmol, 1.00 equiv) was added to 4 M HCl 1,4-dioxanesolution (5.00 mL), and the resulting solution was stirred at 25° C. for1 hour. The residue was purified by reverse flash chromatography withthe following conditions: column, C18 silica gel; mobile phase, MeCN inwater, 10% to 50% gradient in 30 minutes; detector, UV 254 nm to afford8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxylicacid (18 mg, 74.96%) as a yellow solid. ¹H NMR (400 MHz, Methanol-d4) δ7.71 (s, 1H), 6.74 (s, 2H), 4.55-4.26 (m, 4H), 4.07 (d, J=16.9 Hz, 1H),3.96 (s, 6H), 3.66 (s, 3H), 3.47-3.34 (m, 1H), 2.90 (m, 7H). LCMS (ESI)m/z: [M+H]+=402.25.

Example 9—Preparation of and8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N,6-dimethyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxamideand8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxamide(Compounds B3 and B4)

Preparation of8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N,6-dimethyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxamide(Compound B3)

8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxylicacid (30.00 mg, 0.075 mmol, 1.00 equiv), HATU (42.62 mg, 0.112 mmol,1.50 equiv), and methyl amine (4.64 mg, 0.149 mmol, 2.00 equiv), anddiisopropylethylamine (57.9 mg, 0.448 mmol, 6.00 equiv) were dissolvedin DCM (5.0 mL). The resulting solution was stirred at 25° C. for 3hours. The crude product was purified by Prep-HPLC (conditions: C18silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 30minutes; detector, UV 254 nm) to afford8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N,6-dimethyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxamide(6.8 mg, 22%) as a yellow solid. ¹H NMR (400 MHz, Methanol-d4) δ 7.50(s, 1H), 6.62 (s, 2H), 3.88 (s, 6H), 3.85-3.69 (m, 4H), 3.63 (s, 3H),3.52 (dd, J=10.4, 4.8 Hz, 1H), 2.96 (dd, J=17.5, 4.7 Hz, 1H), 2.81 (s,3H), 2.55 (dd, J=17.7, 10.4 Hz, 1H), 2.42 (s, 6H). LCMS (ESI) m/z:[M+H]+=415.30.

Preparation of8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxamide(Compound B4)

8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxylicacid (30.00 mg, 0.075 mmol, 1.00 equiv), HATU (42.62 mg, 0.112 mmol and1.50 equiv), DIEA (57.95 mg, 0.448 mmol, 6.00 equiv) were dissolved inDCM (5.00 mL,). Then NH₃ (2.55 mg, 0.149 mmol, 2.00 equiv) in DCM wasadded to the reaction, and the resulting solution was stirred at 25° C.for 3 hours. The crude product (30 mg) was purified by Prep-HPLC(conditions: C18 silica gel; mobile phase, MeCN in water, 10% to 50%gradient in 30 minutes; detector, UV 254 nm) to afford8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-6-methyl-5-oxo-1,2,3,4,5,6-hexahydro-2,6-naphthyridine-3-carboxamide(4.7 mg, 15.71%) as a yellow solid. ¹H NMR (400 MHz, Methanol-d4) δ 7.50(s, 1H), 6.59 (s, 2H), 3.86 (s, 6H), 3.83-3.66 (m, 4H), 3.63 (s, 3H),3.57 (dd, J=10.4, 4.8 Hz, 1H), 3.05-2.94 (m, 1H), 2.58 (dd, J=17.8, 10.3Hz, 1H), 2.32 (s, 6H). LCMS (ESI) m/z: [M+H]+=401.30.

Example 10—Preparation of5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-N-ethyl-7-methyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide(Compound B5)

Using the same procedure as for the synthesis of Compound B9 andsubstituting with ethyl isocyanate afforded5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-N-ethyl-7-methyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide(18.8 mg, 521% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 7.61(s, 1H), 6.61 (t, J=5.4 Hz, 1H), 6.55 (s, 2H), 4.19 (s, 2H), 3.75 (s,5H), 3.47 (s, 3H), 3.43-3.34 (m, 4H), 3.11-2.97 (m, 2H), 2.09 (s, 6H),1.00 (t, J=7.1 Hz, 3H). LCMS (ESI) m/z: [M+H]⁺=429.2.

Example 11—Preparation of5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-N,N,7-trimethyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide(Compound B6)

To a solution of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(30 mg, 83.9 μmol, 1 equiv) in DCM (1 mL) was added triethylamine (15.1μL, 109 μmol, 1.3 equiv) and N,N-dimethylcarbamoyl chloride (8.48 μL,92.2 μmol, 1.1 equiv) at RT. The reaction was stirred at RT for 2 hours.The reaction mixture was concentrated in vacuo. The crude was purifiedby flash chromatography eluting with 0-15% MeOH with 0.1% NH₄OH in DCMto afford5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-N,N,7-trimethyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide(5.2 mg, 14.5 yield) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ7.14 (s, 1H), 6.40 (s, 2H), 4.33 (s, 2H), 3.83 (s, 6H), 3.58 (s, 3H),3.58 (m, 2H), 3.37 (t, J=5.6 Hz, 2H), 2.89 (s, 5H), 2.63-2.52 (m, 2H),1.25 (s, 6H). LCMS (ESI) m/z: [M+H]⁺=429.2.

Example 12—Preparation ofN-butyl-5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-7-methyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide(Compound B7

Using the same procedure as for the synthesis of Compound B9 andsubstituting with 1-isocyanatobutane affordedN-butyl-5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-7-methyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide(18.8 mg, 49% yield) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ7.18 (s, 1H), 6.37 (s, 2H), 4.68 (t, J=5.5 Hz, 1H), 4.28 (s, 2H), 3.82(s, 6H), 3.61 (s, 3H), 3.61 (m, 2H), 3.53 (s, 1H), 3.28 (td, J=7.1, 5.3Hz, 2H), 2.57 (t, J=5.6 Hz, 2H), 2.30 (s, 6H), 1.59-1.45 (m, 9H),1.43-1.30 (m, 2H), 0.93 (t, J=7.3 Hz, 3H). LCMS (ESI) m/z: [M+H]⁺=457.2.

Example 13—Preparation ofN-cyclopropyl-5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-7-methyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide(Compound B8)

Using the same procedure as for the synthesis of Compound B9 andsubstituting with cyclopropyl isocyanate affordedN-cyclopropyl-5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-7-methyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide(7.8 mg, 21% yield) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ7.18 (s, 1H), 6.37 (s, 2H), 4.93 (d, J=1.9 Hz, 1H), 4.23 (s, 2H), 3.82(s, 6H), 3.60 (d, J=2.2 Hz, 5H), 3.54 (s, 2H), 2.70 (ddd, J=6.9, 4.6,2.7 Hz, 1H), 2.56 (t, J=5.7 Hz, 2H), 2.31 (s, 6H), 1.25 (s, 6H),0.79-0.69 (m, 2H), 0.56-0.38 (m, 2H). LCMS (ESI) m/z: [M+H]⁺=441.2.

Example 14—Preparation of5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide(Compound B9)

To a solution of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(20 mg, 55.9 μmol, 1 equiv) in anhydrous DCM (1 mL) was addedN-methyl-1H-imidazole-1-carboxamide (7.7 mg, 61.4 μmol, 1.1 equiv) andtriethylamine (10 μL, 72.6 μmol, 1.3 equiv). The reaction mixture wasstirred at room temperature for 3 hours and concentrated in vacuo. Thecrude was purified by flash chromatography eluting with 0-15% MeOH w0.1% NH₄OH in DCM to afford5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide(4.0 mg, 18% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 7.60(s, 1H), 6.55 (s, 2H), 6.54 (bs, 1H), 4.19 (s, 2H), 3.75 (s, 6H), 3.47(s, 3H), 3.39 (dd, J=12.4, 7.0 Hz, 4H), 2.57 (d, J=4.3 Hz, 3H), 2.48 (m,2H), 2.10 (s, 6H). LCMS (ESI) m/z: [M+H]⁺=415.3.

Example 15—Preparation ofN-(6-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)acetamide(Compound B10)

Step 1: Preparation of4-bromo-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one (i-21)

To a solution of 4-bromo-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(238 mg, 0.996 mmol, 1 equiv) in AcOH (2.0 mL) was added NaBH₄ (263.64mg, 6.969 mmol, 7 equiv). The mixture was stirred at 0° C. for 1 hour.Ammonium hydroxide was added to the resulting mixture until pH above 7,and then the resulting mixture was extracted with DCM (30 mL×3). Thecombined organic layers were dried over sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withDCM/MeOH (10:1) to afford4-bromo-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one (180 mg,74.38%) as a white solid. LCMS (ESI) m/z: [M+H]⁺=243.

Step 2: Preparation of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(i-22)

To a solution of4-bromo-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one (242 mg,0.995 mmol, 1 equiv) and[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]boronic acid (237.99 mg,0.995 mmol, 1 equiv) in dioxane (5 mL) and H₂O (0.5 mL) was addedPd(dppf)Cl₂ (72.84 mg, 0.100 mmol, 0.1 equiv) and Cs₂CO₃ (973.02 mg,2.986 mmol, 3.0 equiv). The resulting solution was stirred at 90° C. for2 hours under N₂. The mixture was diluted with 50 mL of H₂O, and theresulting mixture was extracted with DCM (30 mL×3). The combined organiclayers were dried over sodium sulfate, and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with DCM/MeOH (10:1) to afford4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(200 mg, 56.21%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=358.

Step 3: Preparation of7-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(i-23)

To a solution of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(200 mg, 0.560 mmol, 1 equiv) and2-[(tert-butyldimethylsilyl)oxy]acetaldehyde (146.30 mg, 0.839 mmol, 1.5equiv) in MeOH (5 mL) was added NaBH₃CN (105.48 mg, 1.679 mmol, 3.0equiv). The mixture was stirred at 25° C. for 1 hour. Then the mixturewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with PE/EtOAc (1:1) to afford7-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(224 mg, 77.5%) as a brown oil. LCMS (ESI) m/z: [M+H]⁺=516.

Step 4: Preparation of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-(2-hydroxyethyl)-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(Compound B10)

To a solution of7-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(90 mg, 0.174 mmol, 1 equiv) was dissolved in ACN (2.0 mL) was addedTBAF (91.25 mg, 0.349 mmol, 2.0 equiv). The resulting solution wasstirred at 25° C. for 1 hour. The mixture was concentrated under reducedpressure. The residue was purified by Prep-(conditions: column, XselectPeptide CSH 19*150 mm 5 μm; Mobile Phase A: Water (0.1% FA), MobilePhase B: MeOH-HPLC; Flow rate: 25 mL/minute; Gradient: 15% B to 15% B in12 minutes; 220 nm; R_(t): 9.51 minutes; detector, UV 254 nm) to affordgave4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-(2-hydroxyethyl)-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(10 mg, 14.27%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 7.51(s, 1H), 6.61 (s, 2H), 3.87 (s, 6H), 3.83-3.72 (m, 4H), 3.60 (d, J=14.7Hz, 5H), 2.79-2.68 (m, 6H), 2.37 (s, 6H). LCMS (ESI) m/z: [M+H]+=402.40.

Example 16—Preparation of Ethyl5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-1,2,3,4,7,8-hexahydro-2,7-naphthyridine-2-carboxylate(Compound B11)

Step 1: Preparation of4-Bromo-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one (i-25)

To a solution of 4-bromo-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(500 mg, 2.091 mmol, 1 equiv) in AcOH (4.20 mL) was added NaBH₄ (553.87mg, 14.640 mmol, 7 equiv) at 0° C. The resulting solution was stirred at0° C. for 1 hour. Ammonia was added to the resulting mixture until pHabove 7. Then the mixture was diluted with water (10 mL) and extractedwith DCM (30 mL×3). The combined organic layers were dried oversaturated sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with DCM/MeOH (10:1) to afford4-bromo-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one (520 mg,74.38%) as a white solid. LCMS (ESI) m/z: [M+H]⁺=243.

Step 2: Preparation of ethyl5-bromo-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate(i-26)

To a solution of4-bromo-2-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-1-one (100.00 mg,0.411 mmol, 1.00 equiv) in (5.00 mL) was added NaH (19.74 mg, 0.494mmol, 1.20 equiv, 60%). Then ethyl chloroformate (66.96 mg, 0.617 mmol,1.50 equiv) was added at 0° C. The resulting mixture was stirred for 2hours at room temperature. The resulting mixture was concentrated underreduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 5:1) toafford ethyl5-bromo-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxylate(120 mg, 92.56%) as a yellow solid. LCMS (ESI) m/z: [M+H]⁺=315.

Step 3: Preparation of ethyl5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-1,2,3,4,7,8-hexahydro-2,7-naphthyridine-2-carboxylate(Compound B11)

To a solution of ethyl5-bromo-7-methyl-8-oxo-1,2,3,4,7,8-hexahydro-2,7-naphthyridine-2-carboxylate(96 mg, 0.305 mmol, 1 equiv) and[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]boronic acid (72.82 mg,0.305 mmol, 1 equiv) in dioxane (2 mL) and H₂O (0.5 mL) was added Cs₂CO₃(297.73 mg, 0.914 mmol, 3 equiv) and Pd(dppf)Cl₂ (33.43 mg, 0.046 mmol,0.15 equiv). The resulting solution was stirred at 90° C. for 2 hours(under N₂ atmosphere). The resulting mixture was concentrated underreduced pressure. The crude product was purified by Prep-HPLC(conditions: XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm; MobilePhase A: Water (0.05% NH₃/H₂O), Mobile Phase B: ACN; Flow rate: 25mL/minute; Gradient: 24% B to 37% B in 8 minutes; 220 nm; Rt: 7.9minutes) to afford ethyl5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-1,2,3,4,7,8-hexahydro-2,7-naphthyridine-2-carboxylate(8.2 mg, 6.09%) as a light brown solid. ¹H NMR (300 MHz, Methanol-d4) δ7.56 (s, 1H), 6.61 (s, 2H), 4.47 (s, 2H), 4.20 (q, J=7.1 Hz, 2H), 3.87(s, 6H), 3.71 (s, 2H), 3.62 (d, J=8.9 Hz, 5H), 2.65 (t, J=5.8 Hz, 2H),2.34 (s, 6H), 1.31 (t, J=7.1 Hz, 3H). LCMS (ESI) m/z: [M+H]⁺=430.20.

Example 17—Preparation of4-(3,5-dimethoxy-4-methylphenyl)-2-methyl-7-propanoyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(Compound B12)

Step 1: Preparation of4-bromo-2-methyl-7-propanoyl-6,8-dihydro-5H-2,7-naphthyridin-1-one(i-28)

To a stirred mixture of4-bromo-2-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-1-one (500.00 mg,2.057 mmol, 1.00 equiv) and propanoic acid (182.83 mg, 2.468 mmol, 1.20equiv) in DCM (25.00 mL) was added DIEA (79.75 mg, 0.617 mmol, 3.00equiv). The mixture was stirred at room temperature for 5 minutes, thenHATU (938.44 mg, 2.468 mmol, 1.20 equiv) was added. The mixture wasstirred for 2 hours at room temperature, and the resulting mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with CH₂Cl₂/MeOH (20:1) to afford4-bromo-2-methyl-7-propanoyl-6,8-dihydro-5H-2,7-naphthyridin-1-one (502mg, 78.88%) as a white solid.

Step 2: Preparation of4-(3,5-dimethoxy-4-methylphenyl)-2-methyl-7-propanoyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(Compound B12)

To a solution of4-bromo-2-methyl-7-propanoyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(200 mg, 0.669 mmol, 1 equiv) and[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]boronic acid (191.80 mg,0.802 mmol, 1.20 equiv) in dioxane (10 mL) and H₂O (1 mL) was addedCs₂CO₃ (653.45 mg, 2.006 mmol, 3.00 equiv) and Pd(dppf)Cl₂.CH₂Cl₂ (49.13mg, 0.060 mmol, 0.09 equiv). After stirring for 2 hours at 90° C. undera nitrogen atmosphere, the resulting mixture was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with DCM/MeOH (10/1) to afford4-(3,5-dimethoxy-4-methylphenyl)-2-methyl-7-propanoyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(130 mg, 51.44%). ¹H NMR (400 MHz, Methanol-d4) δ 7.61 (d, J=10.5 Hz,1H), 6.75 (d, J=6.3 Hz, 2H), 4.56 (d, J=14.2 Hz, 1H), 4.39 (s, 2H), 3.96(d, J=2.6 Hz, 6H), 3.76-3.57 (m, 5H), 2.90 (s, 6H), 2.72 (d, J=6.1 Hz,1H), 2.64 (s, 1H), 2.53 (dq, J=15.0, 7.5 Hz, 1H), 1.31 (s, 1H), 1.17(td, J=7.5, 3.8 Hz, 3H). LCMS (ESI) m/z: [M+H]+=414.30.

Example 18—Preparation of7-acetyl-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(Compound B13)

To a stirred solution of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(45.4 mg, 0.127 mmol, 1 equiv) in DCM (3 mL) was addedisocyanatotrimethylsilane (29.26 mg, 0.254 mmol, 2 equiv) and TEA (38.56mg, 0.381 mmol, 3 equiv). The resulting mixture was stirred for 2 hoursat room temperature. The crude product was purified by Prep-HPLC(conditions: XBridge Prep Phenyl OBD Column 5 μm, 19*250 mm; MobilePhase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 25mL/minute; Gradient: 14% B to 20% B in 8 minutes; 254 nm; R_(t): 7.18minutes) to afford5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-1,2,3,4,7,8-hexahydro-2,7-naphthyridine-2-carboxamide(6.6 mg, 12.35%) as a white solid. ¹H NMR (400 MHz, MeOD) δ 7.57 (s,1H), 6.61 (s, 2H), 4.41 (s, 2H), 3.87 (s, 6H), 3.68 (s, 2H), 3.64 (s,3H), 3.55 (t, 2H), 2.68-2.65 (m, 2H), 2.31 (s, 6H). LCMS (ESI) m/z:[M+H]+=401.4.

Example 19—Preparation of7-acetyl-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(Compound B14)

To the solution of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(35.7 mg, 0.100 mmol, 1 equiv) in DCM (3 mL) was added acetic acid (7.20mg, 0.120 mmol, 1.2 equiv), HATU (56.96 mg, 0.150 mmol, 1.5 equiv), andDIEA (38.72 mg, 0.300 mmol, 3 equiv). The resulting solution was stirredat room temperature for 1 hour. The resulting solution was concentrated.The crude product was purified by Prep-HPLC (conditions: XBridge ShieldRP18 OBD Column, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA),Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient: 0% B to 15% B in8 minutes; 254/220 nm; R_(t): 7.03 minutes) to afford7-acetyl-4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(7.3 mg, 17.64%) as a white solid. ¹H NMR (400 MHz, MeOD) δ 7.58 (d,1H), 6.61 (d, 2H), 4.55 (d, 2H), 3.87 (d, 6H), 3.75-3.67 (m, 3H), 3.64(d, 4H), 2.74 (t, 1H), 2.64 (t, 1H), 2.33 (d, 6H), 2.22 (d, 3H). LCMS(ESI) m/z: [M+H]+=400.25.

Example 20—Preparation of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-ethyl-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-oneformic acid (Compound B15 formic acid)

To the solution of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(20 mg, 0.056 mmol, 1 equiv) in MeOH (2 mL) was added acetaldehyde(24.65 mg, 0.560 mmol, 10 equiv) and NaBH₃CN (10.55 mg, 0.168 mmol, 3equiv). The resulting solution was stirred at room temperature for 1hour. The resulting solution was concentrated. The crude product waspurified by Prep-HPLC (conditions: XBridge Shield RP18 OBD Column, 5 μm,19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flowrate: 25 mL/minute; Gradient: 0% B to 15% B in 8 minutes; 254/220 nm;R_(t): 7.03 minutes) to afford4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-ethyl-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-oneformic acid (10.1 mg) as a white oil. ¹H NMR (400 MHz, Methanol-d4) δ8.47 (s, 1H), 7.59 (s, 1H), 6.73 (s, 2H), 4.38 (s, 2H), 3.96 (s, 6H),3.74 (s, 2H), 3.64 (s, 3H), 2.89 (s, 1 OH), 2.76 (t, J=5.8 Hz, 2H), 1.31(t, J=7.2 Hz, 3H). LCMS (ESI) m/z: [M+H]⁺=386.30.

Example 21—Preparation of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2,7-dimethyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-oneformic acid (Compound B16 formic acid)

To the solution of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(20 mg, 0.056 mmol, 1 equiv) in MeOH (2 mL) was added formaldehyde(16.80 mg, 0.560 mmol, 10 equiv), NaBH₃CN (10.55 mg, 0.168 mmol, 3equiv). The resulting solution was stirred at room temperature for 1hour. The resulting solution was concentrated. The crude product waspurified by Prep-HPLC (conditions: XBridge Shield RP18 OBD Column, 5 μm,19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flowrate: 25 mL/minute; Gradient: 0% B to 15% B in 8 minutes; 254/220 nm;R_(t): 7.12 minutes) to afford4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2,7-dimethyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-oneformic acid (10.8 mg) as a white oil. ¹H NMR (400 MHz, Methanol-d4) δ8.48 (s, 1H), 7.58 (s, 1H), 6.73 (s, 2H), 4.38 (s, 2H), 3.96 (s, 6H),3.67 (s, 2H), 3.63 (s, 3H), 2.89 (s, 6H), 2.84 (t, J=5.7 Hz, 2H), 2.75(d, J=5.8 Hz, 2H), 2.66 (s, 3H). LCMS (ESI) m/z: [M+H]⁺=372.25.

Example 22—Preparation of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(Compound B17)

Step 1: Preparation of2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-2,7-naphthyridin-1-one(i-30)

To the solution of 4-bromo-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(2.7 g, 11.294 mmol, 1 equiv) in dioxane (15 mL) was added4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(3.44 g, 13.552 mmol, 1.2 equiv), Pd(dppf)Cl₂ (0.83 g, 1.129 mmol, 0.1equiv), and AcOK (3.33 g, 33.881 mmol, 3 equiv). The resulting solutionwas stirred at 90° C. for 2 hours under nitrogen atmosphere. Theresulting solution was concentrated. The residue was purified by Flashcolumn chromatography with EtOAc/PE (0-100%) to afford2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-2,7-naphthyridin-1-one(1.62 g, 50.13%) as light yellow solid. LCMS (ESI) m/z: [M+H]+=287.

Step 2: Preparation of2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde(i-31)

To the solution of2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-2,7-naphthyridin-1-one(1.62 g, 5.662 mmol, 1 equiv) in dioxane (30 mL) was added4-bromo-2,6-dimethoxybenzaldehyde (1.39 g, 5.662 mmol, 1 equiv),Pd(dppf)Cl₂ (414.26 mg, 0.566 mmol, 0.1 equiv), Cs₂CO₃ (5.53 g, 16.985mmol, 3 equiv), H₂O (3 mL). The resulting solution was stirred at 90° C.for 2 hours under nitrogen atmosphere. The solution was concentrated.The residue was purified by Flash column chromatography with EtOAc/PE(0-100%) to give compound2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde(1.02 g, 55.55%) as yellow solid. LCMS (ESI) m/z: [M+H]+=325.

Step 3: Preparation of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(i-32)

To the solution of2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde(1.20 g, 3.700 mmol, 1.00 equiv) in MeOH (10.00 mL) was addeddimethylamine (362.02 mg, 4.440 mmol, 1.20 equiv) and NaBH₃CN (697.52mg, 11.100 mmol, 3.00 equiv). The resulting solution was stirred at roomtemperature for 2 hours. The residue was purified by silica gel columnchromatography, eluted with CH₂Cl₂/MeOH (20:1) to afford4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(1 g, 76.48%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=354.

Step 4: Preparation of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(Compound B17)

To a stirred solution of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one(1 g, 2.829 mmol, 1 equiv) in MeOH (15 mL) was added PtO₂ (1 g, 4.404mmol, 1.56 equiv). The resulting mixture was stirred for 6 hours at roomtemperature under hydrogen atmosphere. The resulting mixture wasfiltered, the filter cake was washed with methanol (3×100 mL). Thefiltrate was concentrated under reduced pressure. The crude product waspurified by Prep-HPLC (conditions: XBridge Prep C18 OBD Column, 5 μm,19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flowrate: 25 mL/minute; Gradient: 15% B to 35% B in 8 minutes; 254/220 nm;R_(t): 5.35 minutes) to afford4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(27.2 mg, 2.59%) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ7.54 (s, 1H), 6.55 (s, 2H), 3.77 (s, 6H), 3.60 (s, 2H), 3.46 (s, 3H),3.36 (s, 3H), 2.80 (s, 2H), 2.40 (s, 2H), 2.11 (s, 6H). LCMS (ESI) m/z:[M+H]⁺=358.30.

Example 23—Preparation of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(Compound B17)

Step 1: Preparation of4-bromo-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one (i-34)

To a solution of 4-bromo-1,2-dihydro-2,7-naphthyridin-1-one (4.96 g,22.040 mmol, 1 equiv) and NaH (0.74 g, 30.856 mmol, 1.40 equiv) in DMF(30 mL, 387.653 mmol, 17.59 equiv) was added iodomethane (8.95 g, 63.035mmol, 2.86 equiv). The resulting solution was stirred at 0° C. for 2hours under N₂ atmosphere. The resulting mixture was filtered, and thefilter cake was washed with ice water to afford4-bromo-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one (4.5 g, 76.86%),which was used directly without further purification. LCMS (ESI) m/z:[M+H]+=239.0, 241.0.

Step 2: Preparation of4-bromo-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one (i-35)

NaBH₄(4.43 g, 117.120 mmol, 7 equiv) was slowly added to a solution of4-bromo-2-methyl-1,2-dihydro-2,7-naphthyridin-1-one (4.00 g, 16.731mmol, 1.00 equiv) in AcOH (20.00 mL). The resulting solution was stirredat 0° C. for 1 hour. Ammonia was added to the resulting mixture until pHabove 7. Then the resulting mixture was extracted with DCM (3×30 mL).The combined organic layers were dried over by saturated sodium sulfate.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith DCM/MeOH (10:1) to afford4-bromo-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one (2.2 g,52.64%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=243.0, 245.0.

Step 3: Preparation of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(Compound B17)

To a solution of4-bromo-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one (2.00 g,8.227 mmol, 1.00 equiv) and[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]boronic acid (1.97 g,8.227 mmol, 1.00 equiv) in dioxane (30 mL) and H₂O (6 mL) was addedPd(dppf)Cl₂(0.60 g, 0.823 mmol, 0.1 equiv) and Cs₂CO₃(8.04 g, 24.681mmol, 3.0 equiv). The resulting solution was stirred at 90° C. for 2hours under N₂ atmosphere. The residue was purified by reverse flashchromatography (conditions: column, C18 silica gel; mobile phase, MeOHin water, 10% to 50% gradient in 30 minutes; detector, UV 254 nm) toafford4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(1.54 g, 52.21%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 7.50(s, 1H), 6.59 (s, 2H), 3.88 (s, 1H), 3.86 (s, 6H), 3.81 (s, 2H), 3.64(d, J=14.9 Hz, 5H), 3.63 (s, 1H), 3.55 (s, 1H), 2.99 (dt, J=25.5, 5.8Hz, 2H), 2.60 (dt, J=27.3, 5.7 Hz, 2H), 2.30 (s, 6H). LCMS (ESI) m/z:[M+H]+=358.25.

Example 24—Preparation of8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N,6-dimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(Compound B18)

Step 1: Preparation of 4-bromo-2H-2,6-naphthyridin-1-one (i-37)

To a stirred solution of 2H-2,6-naphthyridin-1-one (584.00 mg, 3.996mmol, 1.00 equiv) in DCM (10.00 mL) was added NBS (640.09 mg, 3.596mmol, 0.9 equiv) in portions at room temperature under air atmosphere.The mixture was stirred for another 1 hour. The reaction mixture wasconcentrated and purified by silica gel column chromatography, elutedwith CH₂Cl₂/MeOH (10:1) to afford 4-bromo-2H-2,6-naphthyridin-1-one (1.2g, 86.74%) as a light yellow solid. LCMS (ESI) m/z: [M+H]+=225, 227.

Step 2: Preparation of 4-bromo-2-methyl-2,6-naphthyridin-1-one (i-38)

To a stirred solution of 4-bromo-2H-2,6-naphthyridin-1-one (600.00 mg,2.666 mmol, 1.00 equiv) in DMF (15.00 mL) was added NaH (127.96 mg,5.332 mmol, 2 equiv) in portions at 0° C. under nitrogen atmosphere.Then Mel (1513.71 mg, 10.665 mmol, 4 equiv) was added drop-wise. Themixture was stirred for another 1 hour at room temperature and quenchedwith water at 0° C. The product was precipitated by the addition ofwater. The precipitated solids were collected by filtration and washedwith water (2×20 mL). The crude product4-bromo-2-methyl-2,6-naphthyridin-1-one (369 mg, 57.89%) was used in thenext step directly without further purification. LCMS (ESI) m/z:[M+H]+=239, 241.

Step 3: Preparation of4-bromo-2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1-one (i-39)

To a stirred solution of 4-bromo-2-methyl-2,6-naphthyridin-1-one (119.50mg, 0.500 mmol, 1.00 equiv) in AcOH (5.00 mL) was added NaBH₄ (132.38mg, 3.499 mmol, 7.00 equiv) in portions at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 5 minutes at roomtemperature. Then, the mixture was poured into ice water, basified withammonium hydroxide, and extracted with CH₂Cl₂ (3×50 mL). The combinedorganic layers were concentrated under reduced pressure and theresulting crude product 4-bromo-2-methyl-5, 6, 7,8-tetrahydro-2,6-naphthyridin-1-one (128 mg, 87.43%) was used directlyin the next step. LCMS (ESI) m/z: [M+H]+=243, 245.

Step 4: Preparation of8-bromo-N,6-dimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(i-40)

To a stirred solution of4-bromo-2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1-one (128.00 mg,0.527 mmol, 1.00 equiv) and N-methylimidazole-1-carboxamide (79.06 mg,0.632 mmol, 1.20 equiv) in DCM (2.00 mL) was added Et₃N (532.79 mg,5.265 mmol, 10 equiv). The resulting mixture was stirred for 2 hours atroom temperature under air atmosphere. The mixture was concentrated andpurified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH(12:1) to afford8-bromo-N,6-dimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(153 mg, 80.35%). LCMS (ESI) m/z: [M+H]+=300, 302.

Step 5: Preparation of8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N,6-dimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(Compound B18)

To a solution of8-bromo-N,6-dimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(153.00 mg, 0.510 mmol, 1.00 equiv) and[[2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]dimethylamine(163.74 mg, 0.510 mmol, 1 equiv) in dioxane (5.00 mL) and H₂O (1.00 mL)was added Cs₂CO₃ (498.25 mg, 1.529 mmol, 3 equiv) and Pd(dppf)Cl₂.CH₂Cl₂(41.63 mg, 0.051 mmol, 0.1 equiv). After stirring for 1.5 hours at 100°C. under a nitrogen atmosphere, the resulting mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography, eluted with CH₂Cl₂/MeOH (12:1) to afford a crudeproduct, and the crude was further purified by Prep-HPLC (conditions:Xselect CSH F-Phenyl OBD column, 19*250, 5 μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute; Gradient:4 B to22 B in 8 minutes; 254/220 nm; R_(T1):6.32 minutes) to afford8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N,6-dimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(49 mg, 23.19%) as a white solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.56(brs, 0.5H, FA), 7.52 (s, 1H), 6.74 (s, 2H), 4.39 (s, 2H), 4.28 (s, 2H),3.96 (s, 6H), 3.67-3.59 (m, 5H), 2.81 (s, 6H), 2.75-2.67 (m, 5H). LCMS(ESI) m/z: [M+H]+=415.35.

Example 25—Preparation ofN-butyl-5-{4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl}-7-methyl-8-oxo-1,2,3,4,7,8-hexahydro-2,7-naphthyridine-2-sulfonamide(compound B19)

Step 1: Preparation of N-butyl-2-oxo-1,3-oxazolidine-3-sulfonamide(i-41)

To a solution of chlorosulfonyl isocyanate (539 μL, 6.21 mmol, 1.00equiv) in dry dichloromethane (8.8 mL) at 0° C. under nitrogenatmosphere was added a solution of 2-chloroethanol (416 μL, 6.21 mmol,1.00 equiv) in dry dichloromethane (2.6 mL) dropwise over 30 minutes.The reaction mixture was then stirred at 0° C. for an additional 30minutes. A solution of butylamine (674 μL, 6.83 mmol, 1.10 equiv) andtriethylamine (1.88 mL, 13.6 mmol, 2.20 equiv) in dry dichloromethane(5.2 mL) was then added dropwise and the reaction mixture was warmed toroom temperature and stirred for 2 hours. Then 1 N aqueous hydrochloricacid was added to adjust the pH to 2. The organic layer was separatedand washed with 1 N aqueous hydrochloric acid (1×7 mL) then water (1×7mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure to afford N-butyl-2-oxo-1,3-oxazolidine-3-sulfonamide (1.49 g,100%) as a white solid. The crude product was used in the next stepwithout further purification.

Step 2: Preparation ofN-butyl-5-{4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl}-7-methyl-8-oxo-1,2,3,4,7,8-hexahydro-2,7-naphthyridine-2-sulfonamide(compound B19)

To a mixture of4-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-2-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-1(2H)-one(48.0 mg, 134.6 μmol, 1.50 equiv) andN-butyl-2-oxo-1,3-oxazolidine-3-sulfonamide (20 mg, 89.8 μmol, 1.00equiv) in dry acetonitrile (0.44 mL) at room temperature was addedtriethylamine (33.6 μL, 242 μmol, 2.70 equiv). The reaction mixture wasstirred at 80° C. for 6 hours. The reaction mixture was then cooled downto room temperature and concentrated under reduced pressure. The residuewas purified by flash silica gel chromatography, elution gradient 0 to100% dichloromethane/methanol/ammonium hydroxide (90:10:1) indichloromethane. Fractions containing the expected product wereevaporated to dryness to afford 15.9 mg of impure product. Purificationby Prep-HPLC (conditions: waters Xterra C18 Column, 19*100 mm, 10 μmparticles; mobile phase A=0.1% ammonium hydroxide in water, mobile phaseB=acetonitrile; flow Rate=40 mL/minute; gradient: 40-82% B in 6 minutes,then a 2 minutes hold at 98% B; wavelength=215 and 254 nm) affordedN-butyl-5-{4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl}-7-methyl-8-oxo-1,2,3,4,7,8-hexahydro-2,7-naphthyridine-2-sulfonamide(3.5 mg, 7.9%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 7.64 (s,1H), 7.36 (s, 1H), 6.57 (s, 2H), 4.00 (s, 2H), 3.77 (s, 6H), 3.49 (s,3H), 3.40 (s, 2H), 3.23 (t, J=5.6 Hz, 2H), 2.89 (t, J=7.0 Hz, 2H), 2.63(t, J=5.4 Hz, 2H), 2.10 (s, 6H), 1.46-1.37 (m, 2H), 1.34-1.25 (m, 2H),0.85 (t, J=7.3 Hz, 3H). LCMS (ESI) m/z: [M+H]+=493.6.

Example 26—Preparation ofN-butyl-5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-7-methyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carbothioamide(compound B20)

4-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-2-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-1(2H)-one(25 mg, 0.069 mmol, 1.00 equiv) was dissolved in dichloromethane.Diisopropylethylamine (0.0126 mL, 0.104 mmol, 1.50 equiv) was then addedfollowed by 1-isothiocyanatobutane (0.0133 ml, 0.0768 mmol, 1.10 equiv).The reaction was allowed to stir at room temperature for 1 hour. Thesolvent was removed under reduced pressure and the resulting oil waspurified by prep-HPLC to obtainN-butyl-5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-7-methyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carbothioamide(30 mg, 47%). ¹H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.80 (t, J=5.3Hz, 1H), 7.65 (s, 1H), 6.59 (s, 2H), 4.59 (s, 2H), 3.87 (q, J=5.1, 4.7Hz, 2H), 3.77 (s, 6H), 3.51 (d, J=15.7 Hz, 7H), 3.15 (s, 1H), 2.57 (t,J=5.6 Hz, 2H), 2.19 (s, 6H), 1.52 (tt, J=8.0, 6.6 Hz, 2H), 1.27 (h,J=7.3 Hz, 2H), 0.87 (t, J=7.3 Hz, 3H). LCMS (ESI) m/z: [M+H]+=473.4.

Example 27—Preparation of8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N,N,6-trimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(compound B21)

Step 1:preparation of8-bromo-N,N,6-trimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(i-42)

Using the same procedure as described in Example 24, step 4 andsubstituting with dimethylcarbamyl chloride (25.8 mg, 0.240 mmol, 1.20equiv) afforded8-bromo-N,N,6-trimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(73 mg, 94%) as an off-white solid. LCMS (ESI) m/z: [M+H]+=314.

Step 2: Preparation of8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N,N,6-trimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(compound B21)

Using the same procedure as described in Example 23, step 2 andsubstituting with8-bromo-N,N,6-trimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(64.2 mg, 0.204 mmol, 1.00 equiv) afforded8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N,N,6-trimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(26.1 mg, 29%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 7.57(s, 1H), 6.60 (s, 2H), 4.00 (s, 2H), 3.78 (s, 6H), 3.48 (s, 3H), 3.46(s, 2H), 3.37 (t, J=5.9 Hz, 2H), 2.70 (s, 6H), 2.57 (t, J=6.0 Hz, 2H),2.14 (s, 6H). LCMS (ESI) m/z: [M+H]+=429.35

Compound B22: LCMS 482.2.

Compound B23: LCMS 511.2; ¹H NMR (400 MHz, DMSO-d6) δ 7.60 (s, 1H), 6.55(s, 3H), 4.19 (s, 2H), 4.06 (d, J=5.3 Hz, 1H), 3.75 (s, 7H), 3.48 (d,J=8.1 Hz, 6H), 3.38 (t, J=5.5 Hz, 2H), 3.24 (s, 1H), 3.15 (d, J=4.6 Hz,2H), 2.96 (s, 0H), 2.57 (d, J=4.2 Hz, 3H), 2.37 (s, 4H), 2.13 (s, 4H).

Example 28—Preparation of5-(4-[[4-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]butanoyl)piperazin-1-yl]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(Compound D1)

Compound D1 was prepared in a similar manner to the preparation ofcompound D2. PyBOP in step 3 was substituted with HATU.5-(4-[[4-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]butanoyl)piperazin-1-yl]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(21.2 mg) was obtained as a white solid. ¹H NMR (300 MHz, Methanol-d4) δ7.80 (t, J=7.9 Hz, 1H), 7.57 (s, 1H), 7.48 (d, J=7.8 Hz, 2H), 6.64 (s,2H), 5.11 (dd, J=12.1, 5.4 Hz, 1H), 4.36 (s, 2H), 4.30 (t, J=5.7 Hz,2H), 4.00 (s, 2H), 3.88 (s, 6H), 3.80-3.69 (m, 4H), 3.64 (s, 3H), 3.53(d, J=5.7 Hz, 2H), 2.94-2.81 (m, 5H), 2.78 (s, 4H), 2.72 (t, J=7.1 Hz,3H), 2.67-2.59 (m, 2H), 2.22-2.09 (m, 3H). LCMS (ESI) m/z:[M+H]+=798.40.

Example 29—Preparation of5-(4-[[4-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetyl)piperazin-1-yl]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(Compound D2)

Step 1: Preparation oftert-butyl4-([2,6-dimethoxy-4-[2-methyl-7-(methylcarbamoyl)-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-4-yl]phenyl]methyl)piperazine-1-carboxylate(i-44)

A mixture of5-(4-formyl-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(400.00 mg, 1.038 mmol, 1.00 equiv) and tert-butylpiperazine-1-carboxylate (193.30 mg, 1.038 mmol, 1.00 equiv) in MeOH (2mL) was stirred for 30 minutes at room temperature under air atmosphere.To the above mixture was added NaBH(AcO)₃ (439.92 mg, 2.076 mmol, 2.00equiv) in portions for 2 hours at room temperature. The resultingmixture was concentrated under vacuum. The residue was purified byreverse flash chromatography (conditions: column, C18 silica gel; mobilephase, MeOH in water, 10% to 50% gradient in 50 minutes; detector, UV254 nm). This resulted intert-butyl4-([2,6-dimethoxy-4-[2-methyl-7-(methylcarbamoyl)-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-4-yl]phenyl]methyl)piperazine-1-carboxylate(300 mg, 52.02%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=556.

Step 2: Preparation of5-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(i-45)

A solution of TFA (1.00 mL) and tert-butyl4-([2,6-dimethoxy-4-[2-methyl-7-(methylcarbamoyl)-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-4-yl]phenyl]methyl)piperazine-1-carboxylate(10.00 mg, 0.018 mmol, 1.00 equiv) in DCM (2.00 mL) was stirred for 1hour at room temperature under air atmosphere. The reaction mixture wasconcentrated under vacuum. The crude product mixture was used in thenext step directly without further purification. LCMS (ESI) m/z:[M+H]+=456.

Step 3:5-(4-[[4-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetyl)piperazin-1-yl]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(Compound D2)

A mixture of[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetic acid(36.47 mg, 0.110 mmol, 1.00 equiv), DIEA (70.93 mg, 0.549 mmol, 5.00equiv), PyBOP (114.23 mg, 0.220 mmol, 2.00 equiv), and[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetic acid(36.47 mg, 0.110 mmol, 1.00 equiv) in DMF (2 mL) was stirred for 2 hoursat room temperature under air atmosphere. The crude product was purifiedby Prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100A, 5 μm, 19mm×250 mm; Mobile Phase A: water (0.1% FA), Mobile Phase B:ACN; Flowrate:25 mL/minute; Gradient:7 B to 20 B in 12 minutes; 254 nm;R_(t):10.95 minutes) to afford5-(4-[[4-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetyl)piperazin-1-yl]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(21.2 mg) as a white solid. ¹H NMR (300 MHz, Methanol-d4) δ 7.85-7.72(m, 1H), 7.61-7.49 (m, 2H), 7.48-7.35 (m, 1H), 6.74 (s, 2H), 5.13 (dd,J=12.2, 5.4 Hz, 3H), 5.04 (d, J=4.2 Hz, 1H), 4.66-4.42 (m, 3H),4.40-4.18 (m, 3H), 3.96 (s, 6H), 3.72-3.62 (m, 4H), 3.61-3.45 (m, 5H),2.96-2.70 (m, 7H), 2.69-2.57 (m, 2H), 2.22-2.09 (m, 1H). LCMS (ESI) m/z:[M+H]⁺=770.55.

Example 30—Preparation of5-(4-[[4-(4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]butanoyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(Compound D3)

Compound D3 was prepared in a similar manner to the preparation ofcompound D4. Compound D3 (19 mg, 19.2%) was obtained as an off-whitesolid. ¹H NMR (300 MHz, Methanol-d4) δ 7.84-7.76 (m, 1H), 7.60 (d, J=7.8Hz, 1H), 7.51-7.43 (m, 2H), 6.71 (d, J=5.0 Hz, 2H), 5.17-5.06 (m, 1H),4.41-4.20 (m, 6H), 3.99-3.86 (m, 6H), 3.83-3.67 (m, 4H), 3.66-3.62 (m,3H), 3.59-3.46 (m, 4H), 2.96-2.69 (m, 8H), 2.69-2.51 (m, 3H), 2.43-1.91(m, 6H), 1.88-1.61 (m, 2H). LCMS (ESI) m/z: [M+H]+=868.80.

Example 31—Preparation of5-(4-[[4-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D4)

Step 1: Preparation of tert-butyl9-([2,6-dimethoxy-4-[2-methyl-7-(methylcarbamoyl)-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-4-yl]phenyl]methyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate(i-47)

Using a similar procedure as described in Example 29, step 1 andsubstituting withtert-butyl1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (93.1 mg,0.363 mmol, 1 equiv affordedtert-butyl9-([2,6-dimethoxy-4-[2-methyl-7-(methylcarbamoyl)-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-4-yl]phenyl]methyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (290 mg,93.1%) as a light brown oil. LCMS (ESI) m/z: [M+H]+=626.

Step 2: Preparation of 5-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(i-48)

Using a similar procedure as described in Example 29, step 2 afforded5-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(114 mg, 46.8%) as a light brown solid. LCMS (ESI) m/z: [M+H]+=526.

Step 3: Preparation of5-(4-[[4-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D4)

Using a similar procedure as described in Example 29, step 3 andsubstituting with5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoicacid (28.5 mg, 0.076 mmol, 1.00 equiv) and5-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(40 mg, 0.076 mmol, 1.00 equiv) afforded5-(4-[[4-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentanoyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (23 mg, 32.6%) as an off-white solid. ¹H NMR (300 MHz,Methanol-d4) δ 8.55 (brs, 0.6H, formic acid), 7.79 (t, J=7.9 Hz, 1H),7.58 (s, 1H), 7.46 (d, J=8.7 Hz, 2H), 6.70 (d, J=5.7 Hz, 2H), 5.15-5.07(m, 1H), 4.39-4.25 (m, 6H), 3.93 (d, J=5.5 Hz, 6H), 3.82-3.72 (m, 2H),3.64 (s, 5H), 3.59-3.50 (m, 4H), 3.31-3.05 (m, 4H), 2.93-2.83 (m, 1H),2.78 (s, 3H), 2.77-2.56 (m, 6H), 2.21-2.03 (m, 3H), 2.01-1.68 (m, 6H).LCMS (ESI) m/z: [M+H]+=882.60.

Example 32—Preparation of5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]amino]ethoxy)ethoxy]ethyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D5 formic acid)

Compound D5 was prepared in a similar manner to the preparation ofcompound D21. Compound D5 formic acid (12.8 mg, 21.5%) was obtained as agreen solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.56 (brs, 1.7H, FA), 7.55(s, 1H), 7.24 (t, J=7.7 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 6.91 (d, J=7.9Hz, 1H), 6.71 (s, 2H), 5.19 (dd, J=13.4, 5.1 Hz, 1H), 4.39-4.27 (m, 5H),4.09-3.98 (m, 2H), 3.94 (s, 6H), 3.67-3.50 (m, 14H), 3.40 (t, J=5.4 Hz,2H), 3.04-2.91 (m, 2H), 2.85 (s, 6H), 2.61 (s, 2H), 2.53-2.39 (m, 1H),2.24-2.12 (m, 1H). LCMS (ESI) m/z: [M−H]⁺=774.37.

Example 33—Preparation of5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[2-[(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethyl)(methyl)amino]ethyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(Compound D6)

Compound D6 was prepared in a similar manner to the preparation ofcompound D21. Compound D6 (2.1 mg, 3.45%) was obtained as a green solid.¹H NMR (300 MHz, Acetonitrile-d3) δ 9.17 (s, 1H), 7.58 (t, J=7.7 Hz,1H), 7.43 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.06 (d, J=7.0 Hz, 1H),6.67-6.47 (m, 4H), 4.95 (dd, J=12.2, 5.2 Hz, 1H), 4.35-4.17 (m, 4H),3.87 (s, 6H), 3.77 (d, J=5.8 Hz, 2H), 3.55 (s, 4H), 3.44-3.24 (m, 5H),2.92 (s, 3H), 2.77 (s, 6H), 2.73-2.60 (m, 3H), 2.54 (s, 2H), 2.30-2.22(m, 1H), 2.14-2.02 (m, 1H). LCMS (ESI) m/z: [M−H]⁺=757.36.

Example 34—Preparation of5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethanesulfonyl)ethyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D7 formic acid)

Compound D7 was prepared in a similar manner to the preparation ofcompound D21. Compound D7 formic acid (13.1 mg, 22.5%) was obtained as agreen solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.56 (brs, 1H, FA),7.66-7.54 (m, 2H), 7.12 (dd, J=17.2, 7.8 Hz, 2H), 6.69 (s, 2H), 5.05(dd, J=12.6, 5.4 Hz, 1H), 4.35 (s, 2H), 4.24 (s, 2H), 3.94 (s, 6H), 3.89(t, J=6.4 Hz, 2H), 3.70 (t, J=6.3 Hz, 2H), 3.63 (s, 3H), 3.49 (t, J=6.3Hz, 4H), 3.42-3.37 (m, 2H), 2.86-2.68 (m, 9H), 2.67-2.60 (m, 3H),2.13-2.01 (m, 1H). LCMS (ESI) m/z: [M+H]+=792.45.

Example 35—Preparation ofN-(2-[[2-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carbonylamino)ethyl](methyl)amino]ethyl)-2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]acetamideformic acid (Compound D8 formic acid)

Compound D7 was prepared in a similar manner to the preparation ofcompound D21. Compound D8 formic acid (10.9 mg, 19.24%) was obtained asa white solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.42 (brs, 2H, FA),7.72-7.63 (m, 1H), 7.51 (s, 1H), 7.43-7.37 (m, 2H), 6.67 (s, 2H), 5.12(dd, J=12.7, 5.4 Hz, 1H), 4.81 (s, 2H), 4.39 (s, 2H), 4.15 (s, 2H), 3.98(s, 6H), 3.63-3.55 (m, 5H), 3.42 (s, 3H), 2.97-2.85 (m, 11H), 2.82-2.63(m, 3H), 2.59 (s, 3H), 2.54-2.39 (m, 2H), 2.21-2.09 (m, 1H). LCMS (ESI)m/z: [M+H]+=815.36.

Example 36—Preparation of5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)-7-methyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamideformic acid (Compound D9 formic acid)

Compound D9 was prepared in a similar manner to the preparation ofcompound D21. Compound D9 formic acid (9.7 mg, 23.93%) was obtained as alight yellow solid. LCMS (ESI) m/z: [M+H]⁺=784.60. ¹H NMR (300 MHz,Methanol-d4) δ 8.56 (br s, 1H, FA), 7.61-7.50 (m, 2H), 6.96 (d, J=2.1Hz, 1H), 6.82 (dd, J=8.4, 2.1 Hz, 1H), 6.69 (s, 2H), 5.05 (dd, J=12.4,5.5 Hz, 1H), 4.36 (s, 2H), 4.21 (s, 2H), 3.93 (s, 6H), 3.63 (s, 3H),3.54 (t, J=5.6 Hz, 2H), 3.25-3.15 (m, 4H), 2.96-2.81 (m, 1H), 2.75 (s,8H), 2.63 (t, J=5.2 Hz, 2H), 2.15-2.03 (m, 1H), 1.73-1.61 (m, 2H),1.60-1.49 (m, 2H), 1.48-1.33 (m, 8H).

Example 37—Preparation of5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-N-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)octyl)-7-methyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamideformic acid (Compound D10 formic acid)

Compound D10 was prepared in a similar manner to the preparation ofcompound D21. Compound D10 formic acid (8.5 mg, 21.8%) was obtained as awhite solid. LCMS (ESI) m/z: [M+H]⁺=842.65. ¹H NMR (300 MHz,Methanol-d4) δ 8.56 (br s, 0.6H, FA), 7.82 (dd, J=8.4, 7.4 Hz, 1H),7.61-7.52 (m, 2H), 7.44 (d, J=8.4 Hz, 1H), 6.71 (s, 2H), 5.15 (dd,J=12.4, 5.5 Hz, 1H), 4.77 (s, 2H), 4.36 (s, 2H), 4.27 (s, 2H), 3.94 (s,6H), 3.64 (s, 3H), 3.54 (t, J=5.6 Hz, 2H), 3.30 (s, 2H), 3.19 (t, J=7.0Hz, 2H), 2.98-2.83 (m, 1H), 2.83-2.70 (m, 8H), 2.64 (t, J=5.4 Hz, 2H),2.22-2.10 (m, 1H), 1.65-1.47 (m, 4H), 1.36 (s, 8H).

Example 38—Preparation of5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-7-methyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamideformic acid (Compound D11 formic acid)

Compound D11 was prepared in a similar manner to the preparation ofcompound D21. Compound D11 formic acid (8.7 mg, 20.7%) was obtained as alight yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.56 (br s, 1H, FA),7.60-7.52 (m, 2H), 7.04 (dd, J=9.4, 7.8 Hz, 2H), 6.71 (s, 2H), 5.04 (dd,J=12.2, 5.4 Hz, 1H), 4.36 (s, 2H), 4.26 (s, 2H), 3.94 (s, 6H), 3.64 (s,3H), 3.53 (t, J=5.6 Hz, 2H), 3.36 (t, J=6.8 Hz, 2H), 3.25 (t, J=6.8 Hz,2H), 2.87-2.72 (m, 8H), 2.70-2.59 (m, 3H), 2.15-2.03 (m, 1H), 1.78-1.66(m, 2H), 1.66-1.56 (m, 2H), 1.56-1.45 (m, 2H). LCMS (ESI) m/z:[M+H]⁺=742.55.

Example 39—Preparation of5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D12 formic acid)

Compound D12 was prepared in a similar manner to the preparation ofcompound D21. Compound D12 formic acid (100 mg, 17.1%) was obtained as ayellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.56 (br s, 0.9H, FA),7.54 (s, 1H), 7.48 (dd, J=8.6, 7.1 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.99(d, J=7.1 Hz, 1H), 6.69 (s, 2H), 5.03 (dd, J=12.5, 5.4 Hz, 1H), 4.34 (s,2H), 4.30 (s, 2H), 3.95 (s, 6H), 3.79 (t, J=5.2 Hz, 2H), 3.72-3.65 (m,4H), 3.64-3.58 (m, 5H), 3.56-3.46 (m, 4H), 3.41 (t, J=5.4 Hz, 2H),2.89-2.79 (m, 7H), 2.77-2.64 (m, 2H), 2.63-2.52 (m, 2H), 2.16-2.05 (m,1H). LCMS (ESI) m/z: [M+H]+=812.45.

Example 40—Preparation of5-(4-[[([[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl]carbamoyl]methyl)(methyl)amino]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(Compound D13)

Step 1: Preparation of2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(i-51)

To a stirred solution of bis(pinacolato)diboron (7.62 g, 29.991 mmol,1.50 equiv) and bis(pinacolato)diboron (7.62 g, 29.991 mmol, 1.50 equiv)in dioxane (70.00 mL) was added Pd(dppf)Cl₂.CH₂Cl₂ (1.63 g, 1.999 mmol,0.10 equiv) and AcOK (5.89 g, 59.982 mmol, 3.00 equiv). The resultingmixture was stirred for 1 hour at 90° C. under nitrogen atmosphere. Thenthe reaction was concentrated and purified by silica gel columnchromatography, eluted with PE/EtOAc (10:1) to afford2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(6.3 g, 92.76%) as an orange solid. LCMS (ESI) m/z: [M+H]+=293.

Step 2: Preparation of5-(4-formyl-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(i-43)

To a stirred solution of2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(291.99 mg, 0.999 mmol, 1.00 equiv) and5-bromo-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(300.00 mg, 0.999 mmol, 1.00 equiv) in dioxane (5.00 mL) and H₂O (0.60mL) was added Cs₂CO₃ (976.95 mg, 2.998 mmol, 3.00 equiv) andPd(dppf)Cl₂.CH₂Cl₂(81.62 mg, 0.100 mmol, 0.1 equiv). After stirring for3 hours at 100° C. under a nitrogen atmosphere, the resulting mixturewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with CH₂Cl₂/MeOH (19:1) toafford5-(4-formyl-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(257 mg, 66.72%) as a brown semi-solid. LCMS (ESI) m/z: [M+H]+=386.

Step 3: Preparation oftert-butyl2-[([2,6-dimethoxy-4-[2-methyl-7-(methylcarbamoyl)-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-4-yl]phenyl]methyl)(methyl)amino]acetate(i-53)

To a stirred solution of5-(4-formyl-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(222.00 mg, 0.576 mmol, 1.00 equiv) and tert-butyl2-(methylamino)acetate hydrochloride (104.64 mg, 0.576 mmol, 1 equiv) inMeOH (5.00 mL) was added NaBH₃CN (72.39 mg, 1.152 mmol, 2 equiv) inportions. The resulting mixture was stirred for 1 hour at roomtemperature under air atmosphere. Then the reaction mixture wasconcentrated, and the resulting residue was purified by silica gelcolumn chromatography, eluted with CH₂Cl₂/MeOH (19:1) to affordtert-butyl2-[([2,6-dimethoxy-4-[2-methyl-7-(methylcarbamoyl)-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-4-yl]phenyl]methyl)(methyl)amino]acetate (268 mg, 90.41%) as a light yellow solid. LCMS (ESI) m/z:[M+H]+=515.

Step 4: Preparation of[([2,6-dimethoxy-4-[2-methyl-7-(methylcarbamoyl)-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-4-yl]phenyl]methyl)(methyl)amino]aceticacid (i-54)

A solution of tert-butyl2-[([2,6-dimethoxy-4-[2-methyl-7-(methylcarbamoyl)-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-4-yl]phenyl]methyl)(methyl)amino]acetate(268.00 mg, 0.521 mmol, 1.00 equiv) and TFA (2.00 mL, 26.926 mmol, 51.70equiv) in DCM (3 mL) was stirred for 1 hour at room temperature underair atmosphere. The reaction mixture was concentrated, and the resultingresidue was purified by reverse flash chromatography (conditions: C18silica gel column; mobile phase, MeCN in water, 10% to 50% gradient in10 minutes; detector, UV 254 nm) to afford[([2,6-dimethoxy-4-[2-methyl-7-(methylcarbamoyl)-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-4-yl]phenyl]methyl)(methyl)amino]acetic acid (135 mg, 56.54%) as a light yellow oil. LCMS(ESI) m/z: [M+H]+=459.

Step 5: Preparation of5-(4-[[([[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl]carbamoyl]methyl)(methyl)amino]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(Compound D13)

To a stirred solution of[([2,6-dimethoxy-4-[2-methyl-7-(methylcarbamoyl)-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-4-yl]phenyl]methyl)(methyl)amino]aceticacid (70.00 mg, 0.153 mmol, 1.00 equiv) and4-[2-(2-aminoethoxy)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(55.17 mg, 0.153 mmol, 1.00 equiv) in DMF (1.00 mL) was added DIEA(98.66 mg, 0.763 mmol, 5.00 equiv) and HATU (116.10 mg, 0.305 mmol, 2.00equiv). The resulting mixture was stirred for 1 hour at roomtemperature. Then the solution was directly purified by Prep-HPLC(conditions: SunFire C18 OBD Prep Column, 100A, 5 μm, 19 mm×250 mm;Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25mL/minute; Gradient: 9% B to 25% B in 12 minutes; 254 nm; R_(t): 10.82minutes) to afford5-(4-[[([[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl]carbamoyl]methyl)(methyl)amino]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(23 mg, 18.79%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.52(br s, 0.4H, FA), 7.66-7.57 (m, 1H), 7.54 (s, 1H), 7.30 (d, J=7.2 Hz,1H), 7.16 (d, J=8.4 Hz, 1H), 6.63 (s, 2H), 5.11 (dd, J=12.8, 5.4 Hz,1H), 4.32 (s, 2H), 4.10-3.93 (m, 4H), 3.90 (s, 6H), 3.65-3.48 (m, 1 OH),3.42-3.37 (m, 3H), 2.88 (dd, J=12.6, 4.6 Hz, 2H), 2.77 (s, 3H), 2.65 (d,J=18.1 Hz, 3H), 2.55-2.48 (m, 3H), 2.07-2.12 (s, 1H). LCMS (ESI) m/z:[M+H]+=802.55.

Example 41—Preparation of5-[4-[(dimethylamino)methyl]-2,5-dimethoxyphenyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D14 formic acid)

To a stirred solution of triphosgene (13.2 mg, 0.044 mmol, 0.40 equiv)in DCM (1 mL) was added a solution of4-[[2-(2-aminoethoxy)ethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(40.0 mg, 0.111 mmol, 1.00 equiv) and TEA (50 uL) in DCM (0.6 mL)dropwise at 0° C. After 2 minutes, additional TEA (30 uL) was addeddropwise. The resulting mixture was stirred for additional 10 minutes at0° C.4-[4-[(dimethylamino)methyl]-2,5-dimethoxyphenyl]-2-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-1-one(39.7 mg, 0.111 mmol, 1.00 equiv) was then added in one portion. Thereaction was stirred for additional 5 minutes at 0° C. and then warmedto room temperature for 25 minutes. The reaction solution wasconcentrated under vacuum. The crude product was purified by Prep-HPLC(conditions: SunFire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250 mm;Mobile Phase A: water (0.1% FA), Mobile Phase B:ACN; Flow rate:25mL/minute; Gradient:9 B to 19 B in 14 minutes; 254 nm; RT:15.53 minutes)to afford5-[4-[(dimethylamino)methyl]-2,5-dimethoxyphenyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (5.9 mg, 6%) as a yellow solid. ¹H NMR (400 MHz,Methanol-d4) δ 8.56 (s, 0.4H, FA), 7.56 (dd, J=8.6, 7.1 Hz, 1H), 7.44(s, 1H), 7.11 (d, J=9.3 Hz, 2H), 7.03 (d, J=7.0 Hz, 1H), 6.95 (s, 1H),5.04 (dd, J=12.4, 5.4 Hz, 1H), 4.36 (br s, 2H), 4.09 (s, 2H), 3.89 (s,3H), 3.81-3.70 (m, 6H), 3.66-3.56 (m, 6H), 3.51 (t, J=5.2 Hz, 2H), 3.43(t, J=5.3 Hz, 2H), 2.89-2.62 (m, 9H), 2.53 (br s, 1H), 2.32 (br s, 1H),2.11-2.02 (m, 1H). LCMS (ESI) m/z: [M+H]+=744.50.

Example 42—Preparation of5-(4-[[3-(6-[[2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]hexanamido)azetidin-1-yl]methyl]-2,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D15 formic acid)

Step 1: Preparation of 4-Formyl-2,5-dimethoxyphenylboronic acid (i-58)

To a stirred solution of 4-bromo-2,5-dimethoxybenzaldehyde (200.00 mg,0.816 mmol, 1.00 equiv) and bis(pinacolato)diboron (248.68 mg, 0.979mmol, 1.2 equiv) in dioxane (2 mL) was added KOAc (160.19 mg, 1.632mmol, 2 equiv) and Pd(dppf)Cl₂ (59.71 mg, 0.082 mmol, 0.1 equiv). Themixture was stirred at 90° C. for 1 hour (under N₂ atmosphere). Theresulting mixture was concentrated under reduced pressure to afford4-formyl-2,5-dimethoxyphenylboronic acid (400 mg, crude) as a brownsolid. The crude product was used in the next step directly withoutfurther purification. LCMS (ESI) m/z: [M+H]+=211.3.

Step 2: Preparation of5-(4-Formyl-2,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(i-59)

To a stirred solution of 4-formyl-2,5-dimethoxyphenylboronic acid(107.00 mg, 0.510 mmol, 1.00 equiv) and5-bromo-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(152.94 mg, 0.510 mmol, 1.00 equiv) in dioxane (1.00 mL) and H₂O (5.00mL) was added CS₂CO₃ (332.04 mg, 1.019 mmol, 2 equiv) and Pd(dppf)Cl₂(37.28 mg, 0.051 mmol, 0.1 equiv). The mixture was stirred at 90° C. for1 hour (under N₂ atmosphere). The resulting mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford5-(4-formyl-2,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(247 mg, crude) as a brown solid. LCMS (ESI) m/z: [M+H]+=386.2.

Step 3: Preparation of tert-ButylN-[1-([2,5-dimethoxy-4-[2-methyl-7-(methylcarbamoyl)-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-4-yl]phenyl]methyl)azetidin-3-yl]carbamate(i-60)

To a stirred solution of5-(4-formyl-2,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(100.00 mg, 0.259 mmol, 1.00 equiv) and tert-butylN-(azetidin-3-yl)carbamate (44.69 mg, 0.259 mmol, 1 equiv) in MeOH (2.00mL) was added NaBH(OAc)₃ (109.98 mg, 0.519 mmol, 2 equiv). The mixturewas stirred at room temperature for 1 h. The resulting mixture wasconcentrated under vacuum. The residue was purified by Prep-TLC(CH₂Cl₂/MeOH 10:1) to afford tert-butylN-[1-([2,5-dimethoxy-4-[2-methyl-7-(methylcarbamoyl)-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-4-yl]phenyl]methyl)azetidin-3-yl]carbamate(100 mg, 71.16%) as a brown solid. LCMS (ESI) m/z: [M+H]+=542.2

Step 4: Preparation of afford5-[4-[(3-Aminoazetidin-1-yl)methyl]-2,5-dimethoxyphenyl]-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(i-61)

To a stirred solution of tert-butylN-[1-([2,5-dimethoxy-4-[2-methyl-7-(methylcarbamoyl)-1-oxo-6,8-dihydro-5H-2,7-naphthyridin-4-yl]phenyl]methyl)azetidin-3-yl]carbamate(100.00 mg, 0.185 mmol, 1.00 equiv) in DCM (2.00 mL,) was added TFA(0.40 mL). The resulting mixture was concentrated under reduced pressureto afford5-[4-[(3-aminoazetidin-1-yl)methyl]-2,5-dimethoxyphenyl]-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(80 mg, 98.14%) as a yellow solid. The crude product was used in thenext step directly without further purification. LCMS (ESI) m/z:[M+H]+=442.2.

Step 5: Preparation of afford5-(4-[[3-(6-[[2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]hexanamido)azetidin-1-yl]methyl]-2,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D15 formic acid)

To a solution of5-[4-[(3-aminoazetidin-1-yl)methyl]-2,5-dimethoxyphenyl]-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(70.00 mg, 0.159 mmol, 1.00 equiv) and6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]hexanoic acid(61.57 mg, 0.159 mmol, 1.00 equiv) in DMF (1 mL) was added DIEA (102.45mg, 0.793 mmol, 5.00 equiv) and HATU (90.42 mg, 0.238 mmol, 1.50 equiv).The resulting solution was stirred at room temperature for 1 hour.Without any additional work-up, the mixture was purified by prep-HPLC(conditions: SunFire C18 OBD Prep Column, 100A, 5 μm, 19 mm×250 mm;Mobile Phase A: water (0.1% FA), Mobile Phase B:ACN; Flow rate:25mL/minute; Gradient:9 B to 23 B in 14 minutes; 254 nm; R_(t): 14.33minutes) to give5-(4-[[3-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]hexanamido)azetidin-1-yl]methyl]-2,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (9.7 mg, 6.84%) as a white solid. ¹H NMR (400 MHz,Methanol-d4) δ 8.49 (br s, 1H, FA), 7.78 (dd, J=8.4, 7.4 Hz, 1H),7.49-7.41 (m, 3H), 7.06 (s, 1H), 6.88 (s, 1H), 5.10 (dd, J=12.5, 5.5 Hz,1H), 4.55-4.44 (m, 1H), 4.34 (s, 2H), 4.25 (t, J=6.1 Hz, 2H), 4.11 (s,2H), 4.06 (t, J=8.5 Hz, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 3.74-3.64 (m,3H), 3.61 (s, 3H), 2.95-2.65 (m, 6H), 2.52 (s, 2H), 2.29 (t, J=7.3 Hz,2H), 2.18-2.07 (m, 1H), 1.96-1.85 (m, 2H), 1.81-1.69 (m, 2H), 1.66-1.54(m, 2H). LCMS (ESI) m/z: [M+H]+=812.45.

Example 43—Preparation of5-(4-[[3-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]hexanamido)azetidin-1-yl]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D16 formic acid)

Compound D16 was prepared in a similar manner to the preparation ofcompound D21. 15 Compound D16 formic acid (15 mg, 40.8%) was obtained asa white solid. ¹H NMR (400 MHz, Methanol-d4) δ 8.52 (br s, 1H, FA), 7.78(dd, J=8.4, 7.3 Hz, 1H), 7.56 (s, 1H), 7.45 (dd, J=7.8, 2.7 Hz, 2H),6.68 (s, 2H), 5.10 (dd, J=12.4, 5.5 Hz, 1H), 4.55-4.46 (m, 1H),4.41-4.32 (m, 4H), 4.25 (t, J=6.1 Hz, 2H), 4.19 (s, 2H), 3.92 (s, 7H),3.64 (s, 3H), 3.54 (t, J=5.6 Hz, 2H), 2.89-2.66 (m, 6H), 2.62 (t, J=5.6Hz, 2H), 2.29 (t, J=7.3 Hz, 2H), 2.17-2.08 (m, 1H), 1.94-1.85 (m, 2H),1.79-1.71 (m, 2H), 1.66-1.55 (m, 2H). LCMS (ESI) m/z: [M+H]+=812.45.

Example 44—Preparation of5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D17 Formic Acid)

Compound D17 formic acid was prepared in a similar manner to thepreparation of compound D21. Compound D17 formic acid (75.8 mg, 22%) wasobtained as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.57 (s,0.1H, FA), 7.62-7.50 (m, 2H), 7.11 (d, J=8.5 Hz, 1H), 7.03 (d, J=7.1 Hz,1H), 6.72 (s, 2H), 5.03 (dd, J=12.3, 5.3 Hz, 1H), 4.38 (s, 2H), 4.27 (s,2H), 3.94 (s, 6H), 3.74 (t, J=5.0 Hz, 2H), 3.67-3.61 (m, 5H), 3.51 (q,J=4.9 Hz, 4H), 3.44 (t, J=5.3 Hz, 2H), 2.80 (s, 7H), 2.78-2.56 (m, 4H),2.13-2.00 (m, 1H). LCMS (ESI) m/z: [M+H]+=744.45.

Example 45—Preparation of5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]pentyl)-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(Compound D18)

Compound D18 was prepared in a similar manner to the preparation ofcompound D21. Compound D18 (5 mg, 12.10%) was obtained as a yellowsolid. ¹H NMR (300 MHz, Methanol-d4) δ 7.78 (dd, J=8.5, 7.2 Hz, 1H),7.59 (s, 1H), 7.46 (d, J=1.7 Hz, 1H), 7.43 (s, 1H), 6.74 (s, 2H), 5.12(dd, J=12.3, 5.4 Hz, 1H), 4.38 (s, 4H), 4.26 (t, J=6.1 Hz, 2H), 3.96 (s,6H), 3.63 (s, 3H), 3.54 (d, J=5.6 Hz, 2H), 3.27 (t, J=6.6 Hz, 1H), 2.89(s, 7H), 2.90-2.79 (m, 1H), 2.79-2.59 (m, 3H), 2.18-2.05 (m, 1H),1.97-1.86 (m, 2H), 1.65 (s, 5H). LCMS (ESI) m/z: [M+H]⁺=743.65.

Example 46—Preparation of4-[[9-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-1,2,3,4,7,8-hexahydro-2,7-naphthyridin-2-yl)-9-oxononyl]amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(Compound D19)

To a stirred solution of9-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino]nonanoicacid (100 mg, 0.233 mmol, 1 equiv) in DMF (2 mL) was added HATU (115.02mg, 0.303 mmol, 1.3 equiv) and DIEA (150.46 mg, 1.164 mmol, 5.0 equiv).The mixture was stirred at 25° C. for 30 minutes, and then4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-1-one(83.23 mg, 0.233 mmol, 1 equiv) was added. The mixture was stirred at25° C. for 2 hours. Then the mixture was diluted with water (20 mL) andextracted with DCM (20 mL×3). The organic layers were combined andwashed with saturated sodium chloride (20 mL), then dried over anhydroussodium sulfate, filtered, and concentrated to give a crude product. Theresidue was purified by Prep-HPLC (condition: XSelect CSH Prep C18 OBDColumn, 5 μm, 19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile PhaseB: ACN; Flow rate: 25 mL/minute; Gradient: 20% B to 40% B in 8 minutes;254/220 nm; R_(t): 7.08 minutes; Detector, 254 nm) to give4-[[9-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-1,2,3,4,7,8-hexahydro-2,7-naphthyridin-2-yl)-9-oxononyl]amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione(25 mg, 32.5 μmol, 13.96%) as a yellow solid. ¹H NMR (400 MHz,Methanol-d4) δ 7.64-7.51 (m, 2H), 7.04 (dd, J=7.9, 6.2 Hz, 2H), 6.72 (d,J=5.9 Hz, 2H), 5.12-5.01 (m, 1H), 4.62 (s, 2H), 4.55 (d, J=5.5 Hz, 2H),4.33 (d, J=11.1 Hz, 2H), 3.95 (d, J=1.9 Hz, 6H), 3.75-3.63 (m, 5H), 2.86(d, J=2.3 Hz, 7H), 2.80-2.68 (m, 3H), 2.67-2.59 (m, 1H), 2.50 (dt,J=17.8, 7.6 Hz, 2H), 2.17-2.08 (m, 1H), 1.67 (dd, J=13.6, 6.8 Hz, 4H),1.45-1.31 (m, 8H). LCMS (ESI) m/z: [M+H]+=769.70.

Example 47—Preparation of([4-[7-(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]hexanoyl)-2-methyl-1-oxo-1,2,5,6,7,8-hexahydro-2,7-naphthyridin-4-yl]-2,6-dimethoxyphenyl]methyl)(methyl)aminyl(Compound D20)

Compound D20 was prepared in a similar manner to the preparation ofcompound D19 and by substituting the carboxylic acid i-36 with6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy]hexanoicacid (130 mg, 0.336 mmol, 1.20 equiv) in dimethylformamide (3.0 mL).Compound D20 (7.8 mg, 3.74%) was obtained as a white solid. ¹H NMR (400MHz, Methanol-d4) δ 8.56 (s, 1H), 7.76 (td, J=7.9, 3.5 Hz, 1H), 7.59 (d,J=12.7 Hz, 1H), 7.43 (q, J=5.8 Hz, 2H), 6.71 (s, 2H), 5.08 (dd, J=12.6,5.5 Hz, 1H), 4.55 (s, 2H), 4.25 (dt, J=6.5, 3.2 Hz, 4H), 3.93 (d, J=4.5Hz, 6H), 3.70 (dt, J=10.4, 5.6 Hz, 2H), 3.63 (d, J=2.9 Hz, 3H), 2.78 (d,J=6.0 Hz, 7H), 2.66 (s, 2H), 2.77-2.51 (m, 4H), 2.11 (tdd, J=10.7, 5.9,3.1 Hz, 1H), 1.91 (h, J=6.4 Hz, 2H), 1.76 (p, J=7.5 Hz, 2H), 1.70-1.57(m, 2H). LCMS (ESI) m/z: [M+H]⁺=728.50.

Example 48—Preparation of5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]ethoxy)ethyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D21 formic acid)

Step 1: Preparation of tert-butylN-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]ethoxy)ethyl]carbamate (i-65)

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.00 g, 3.620mmol, 1.00 equiv) and tert-butyl N-[2-(2-aminoethoxy)ethyl]carbamate(1.48 g, 7.241 mmol, 2.00 equiv) in NMP (10 mL) was added DIEA (935.79mg, 7.241 mmol, 2.00 equiv) at room temperature. The resulting mixturewas stirred for 4 hours at 90° C. under nitrogen atmosphere. The residuewas purified by reverse flash chromatography (conditions: column, C18silica gel; mobile phase, ACN in water, 0% to 50% gradient in 20minutes; detector, UV 254 nm). This resulted in tert-butylN-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]ethoxy)ethyl]carbamate(430 mg, 25.79%) as a yellow oil. LCMS (ESI) m/z: [M+H]+=461.20.

Step 2: Preparation of5-[[2-(2-aminoethoxy)ethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(i-66)

A solution of tert-butylN-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]ethoxy)ethyl]carbamate (400.00 mg, 0.869 mmol, 1.00 equiv) and TFA (1.00 mL) in DCMwas stirred for 2 hours at room temperature. The resulting mixture wasconcentrated under vacuum. This resulted in5-[[2-(2-aminoethoxy)ethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(220 mg, 70.28%) as a brown solid. LCMS (ESI) m/z: [M+H]+=361.14.

Step 3: Preparation of5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]ethoxy)ethyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D21 formic acid)

A solution of5-[[2-(2-aminoethoxy)ethyl]amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione(60.00 mg, 0.166 mmol, 1.00 equiv) and CDI (29.70 mg, 0.183 mmol, 1.10equiv) in acetonitrile (1.5 mL) and DMF (0.3 mL) was stirred for 2 hoursat room temperature. Then4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-1-one(119.03 mg, 0.333 mmol, 2.00 equiv) and TEA (33.70 mg, 0.333 mmol, 2.00equiv) was added to the reaction mixture. The resulting mixture wasstirred for overnight at room temperature. The crude product waspurified by Prep-HPLC (conditions: SunFire C18 OBD Prep Column, 100A, 5μm, 19 mm×250 mm; mobile phase, Water (0.05% TFA) and ACN (12% Phase Bup to 26% in 15 minutes); Detector, UV). This resulted in5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]ethoxy)ethyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(4 mg, 3.23%) as a green semi-solid. ¹H NMR (400 MHz, Acetonitrile-d3) δ9.31 (s, 1H), 9.03 (brs, 1.0H, FA), 7.51 (d, J=8.3 Hz, 1H), 7.40 (s,1H), 7.00 (d, J=2.1 Hz, 1H), 6.91 (dd, J=8.3, 2.2 Hz, 1H), 6.60 (s, 2H),6.18 (s, 1H), 5.67 (t, J=5.7 Hz, 1H), 4.92 (dd, J=12.5, 5.4 Hz, 1H),4.28 (d, J=4.8 Hz, 4H), 3.85 (s, 6H), 3.71 (t, J=5.0 Hz, 2H), 3.58-3.49(m, 7H), 3.39 (q, J=5.3 Hz, 2H), 3.34 (t, J=5.0 Hz, 2H), 2.77 (s, 6H),2.75-2.65 (m, 2H), 2.57 (t, J=5.6 Hz, 2H), 1.35-1.24 (m, 1H). LCMS (ESI)m/z: [M+H]⁺=744.50.

Example 49—Preparation of5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-(5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]pentyl)-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D22 formic acid)

Compound D22 formic acid was prepared in a similar manner to thepreparation of compound D21. Compound D22 formic acid (8.7 mg, 20.8%)was obtained as a light yellow solid. ¹H NMR (400 MHz, Methanol-d4) δ8.57 (brs, 0.7H, FA), 7.79 (d, J=8.3 Hz, 1H), 7.58 (s, 1H), 7.37 (d,J=2.2 Hz, 1H), 7.31 (dd, J=8.3, 2.3 Hz, 1H), 6.66 (s, 2H), 5.10 (dd,J=12.6, 5.4 Hz, 1H), 4.36 (s, 2H), 4.17 (t, J=6.3 Hz, 2H), 4.10 (s, 2H),3.91 (s, 6H), 3.64 (s, 3H), 3.54 (t, J=5.6 Hz, 2H), 3.27 (t, J=6.6 Hz,2H), 2.93-2.70 (m, 3H), 2.70-2.58 (m, 8H), 2.17-2.07 (m, 1H), 1.89 (p,J=6.5 Hz, 2H), 1.70-1.52 (m, 4H). LCMS (ESI) m/z: [M+H]⁺=743.35.

Example 50—Preparation of8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]-6-methyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamideformic acid (Compound D23 formic acid)

Step 1: Preparation of 4-bromo-2H-2,6-naphthyridin-1-one (i-68)

To a stirred solution of 2H-2,6-naphthyridin-1-one (584.00 mg, 3.996mmol, 1.00 equiv) in DCM (10.00 mL) was added NBS (640.09 mg, 3.596mmol, 0.9 equiv) in portions at room temperature under air atmosphere.The mixture was stirred for another 1 hour. The reaction mixture wasconcentrated and purified by silica gel column chromatography, elutedwith CH₂Cl₂/MeOH (12:1) to afford 4-bromo-2H-2,6-naphthyridin-1-one(1.18 g, 85.29%) as a light yellow solid. LCMS (ESI) m/z: [M+H]+=225,227.

Step 2: Preparation of 4-bromo-2-methyl-2,6-naphthyridin-1-one (i-69)

To a stirred solution of 4-bromo-2H-2,6-naphthyridin-1-one (1.18 g,5.243 mmol, 1.00 equiv) in Mel (2.98 g, 20.974 mmol, 4.00 equiv) wasadded NaH (0.25 g, 10.487 mmol, 2.00 equiv) in portions at 0° C. undernitrogen atmosphere. Then Mel (1513.71 mg, 10.665 mmol, 4 equiv) wasadded drop-wise. The mixture was stirred for another 1 hour at roomtemperature and quenched with water at 0° C. The product wasprecipitated by the addition of water. The precipitated solids werecollected by filtration and washed with water (2×20 mL). The crudeproduct 4-bromo-2-methyl-2, 6-naphthyridin-1-one (568 mg, 45.31%) wasused in the next step directly without further purification. LCMS (ESI)m/z: [M+H]+=239, 241.

Step 3: Preparation of4-bromo-2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1-one (i-70)

To a stirred solution of 4-bromo-2-methyl-2, 6-naphthyridin-1-one(239.10 mg, 1.000 mmol, 1.00 equiv) in AcOH (5.00 mL) was added NaBH₄(264.86 mg, 7.001 mmol, 7.00 equiv) in portions at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 5 minutes at roomtemperature. Then, the mixture was poured into ice water, basified withammonium hydroxide, and extracted with CH₂Cl₂ (3×50 mL). The combinedorganic layers were concentrated under reduced pressure and theresulting crude product4-bromo-2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1-one (237 mg,80.91%) was used directly in the next step. LCMS (ESI) m/z: [M+H]+=243,245.

Step 4: Preparation of4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1-one(i-72)

To a solution of4-bromo-2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1-one (237.00 mg,0.975 mmol, 1.00 equiv) and[[2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]dimethylamine (313.15 mg, 0.975 mmol, 1 equiv) in dioxane (5.00 mL) and H₂O(1.00 mL) was added Cs₂CO₃ (952.92 mg, 2.925 mmol, 3 equiv) andPd(dppf)Cl₂.CH₂Cl₂(79.61 mg, 0.097 mmol, 0.1 equiv). After stirring for1.5 h at 100° C. under a nitrogen atmosphere, the resulting mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with CH₂Cl₂/MeOH (12:1) to afford thecrude product,4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1-one(524 mg, 79.69%) as a dark brown solid. LCMS (ESI) m/z: [M+H]+=358.

Step 5: Preparation of8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]-6-methyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamideformic acid (Compound D23 formic acid)

To a stirred solution of4-([2-[2-(2-aminoethoxy)ethoxy]ethyl]amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dionetrifluoroacetic acid salt (40.40 mg, 0.078 mmol, 1.00 equiv) in DMF(0.30 mL) and MeCN (0.90 mL) was added CDI (13.90 mg, 0.086 mmol, 1.10equiv). The mixture was stirred for 2 hours at room temperature underair atmosphere. Then4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1-one(41.78 mg, 0.117 mmol, 1.50 equiv) and Et₃N (23.66 mg, 0.234 mmol, 3.00equiv) was added, and the final reaction mixture was stirred forovernight at room temperature under air atmosphere. Without anyadditional work-up, the resulting mixture was purified by Prep-HPLC(conditions: Xselect CSH F-Phenyl OBD Column 19*150 mm 5 μm; MobilePhase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/minute;Gradient: 9 B to 20 B in 10 minutes; 254 nm; R_(t1):9.75 minutes) toafford8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[2-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethoxy]ethyl]-6-methyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(21 mg, 33.49%) as a yellow solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.57(brs, 0.7H, FA), 7.58-7.48 (m, 2H), 7.07 (dd, J=14.0, 7.8 Hz, 2H), 6.71(s, 2H), 5.03 (dd, J=12.4, 5.4 Hz, 1H), 4.36 (s, 2H), 4.19 (s, 2H), 3.94(s, 6H), 3.73 (t, J=5.2 Hz, 2H), 3.68-3.57 (m, 9H), 3.57-3.47 (m, 4H),3.35 (s, 1H), 2.92-2.75 (m, 2H), 2.74 (s, 6H), 2.71-2.58 (m, 4H),2.14-2.04 (m, 1H). LCMS (ESI) m/z: [M+H]+=788.50.

Example 51—Preparation of8-(4-(((2-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethyl)amino)-2-oxoethyl)(methyl)amino)methyl)-3,5-dimethoxyphenyl)-N,6-dimethyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2(1H)-carboxamide(Compound D24)

Compound D24 was prepared in a similar manner to the preparation ofcompound D13 and compound D23.

Example 52—Preparation of5-[4-[(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]-N-methylhexanamido)methyl]-3,5-dimethoxyphenyl]-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(Compound D25)

Step 1: Preparation of5-bromo-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(1-75)

Using a similar procedure as described in Example 24, step 4 andsubstituting with4-bromo-2-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-1-one (243 mg,1.000 mmol) afforded5-bromo-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(348 mg, 98.6%) as a light yellow solid. LCMS (ESI) m/z: [M+H]+=300,302.

Step 2: Preparation of5-(4-formyl-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(i-76)

Using a similar procedure as described in Example 23, step 3 andsubstituting with5-bromo-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(100 mg, 0.333 mmol, 1.00 equiv) and2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(97.3 mg, 0.333 mmol, 1.00 equiv) afforded5-(4-formyl-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(132 mg, 91.5%) as a light yellow solid. LCMS (ESI) m/z: [M+H]+=386.

Step 3: Preparation of5-[3,5-dimethoxy-4-[(methylamino)methyl]phenyl]-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(i-77)

To a stirred solution of5-(4-formyl-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(100 mg, 0.259 mmol, 1.00 equiv) and triethylamine (78.76 mg, 0.778mmol, 3.00 equiv) in methanol (1.00 mL) was added sodiumcyanoborohydride (32.6 mg, 0.519 mmol, 2.00 equiv) in portions at roomtemperature. Solvent was then evaporated under reduced pressure and theresidue was purified by silica gel column chromatography, eluted withdichloromethane/methanol (12:1) to afford5-[3,5-dimethoxy-4-[(methylamino)methyl]phenyl]-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(71 mg, 68.3%) as a yellow solid. LCMS (ESI) m/z: [M+H]+=400.

Step 4: Preparation of5-[4-[(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]-N-methylhexanamido)methyl]-3,5-dimethoxyphenyl]-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(Compound D25)

Using a similar procedure as described in Example 46 and substitutingwith5-[3,5-dimethoxy-4-[(methylamino)methyl]phenyl]-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(60 mg, 0.150 mmol, 1.00 equiv) and6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]hexanoic acid(58.2 mg, 0.150 mmol, 1.00 equiv) afforded5-[4-[(6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]-N-methylhexanamido)methyl]-3,5-dimethoxyphenyl]-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(30 mg, 25.5%) as an off-white solid. ¹H NMR (300 MHz, Methanol-d4) δ7.76 (dd, J=8.6, 7.2 Hz, 1H), 7.55 (d, J=2.8 Hz, 1H), 7.49-7.37 (m, 2H),6.60 (d, J=14.9 Hz, 2H), 5.08 (dd, J=12.3, 5.5 Hz, 1H), 4.76-4.57 (m,2H), 4.35 (s, 2H), 4.25 (t, J=6.1 Hz, 2H), 3.85 (d, J=11.5 Hz, 6H), 3.63(d, J=3.6 Hz, 3H), 3.52 (q, J=5.2 Hz, 2H), 2.83 (d, J=2.0 Hz, 4H), 2.77(d, J=6.8 Hz, 4H), 2.72-2.55 (m, 4H), 2.51-2.39 (m, 1H), 2.20-2.00 (m,1H), 1.87 (d, J=7.8 Hz, 2H), 1.66 (dd, J=21.4, 2.6 Hz, 4H). LCMS (ESI)m/z: [M+H]+=771.40.

Example 53—Preparation of5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[1-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy]ethyl)piperidin-4-yl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D26 formic acid)

Compound D26 was prepared in a similar manner to the preparation ofcompound D21. Compound D26 formic acid (4.5 mg, 4.68%) was obtained as awhite solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.48 (brs, 1.6H, FA), 7.85(d, J=8.3 Hz, 1H), 7.60 (s, 1H), 7.49 (d, J=2.2 Hz, 1H), 7.39 (dd,J=8.3, 2.3 Hz, 1H), 6.74 (s, 2H), 5.13 (dd, J=12.3, 5.4 Hz, 1H), 4.39(d, J=3.8 Hz, 6H), 3.95 (s, 6H), 3.78-3.68 (m, 1H), 3.64 (s, 3H), 3.56(t, J=5.5 Hz, 2H), 3.29-3.22 (m, 2H), 3.13 (s, 2H), 2.89 (s, 6H),2.86-2.71 (m, 3H), 2.69-2.54 (m, 4H), 2.22-2.09 (m, 1H), 2.01 (d, J=13.0Hz, 2H), 1.81-1.64 (m, 2H). LCMS (ESI) m/z: [M+H]⁺=784.45.

Example 54—Preparation of8-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy)ethyl]-6-methyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamideformic acid (Compound D27 formic acid)

Compound D27 was prepared in a similar manner to the preparation ofcompound D23. Compound D27 formic acid (21 mg, 35.8%) was obtained as ayellow solid. ¹H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.19 (brs,0.4H, FA), 7.63-7.52 (m, 2H), 7.13 (d, J=8.6 Hz, 1H), 7.04 (d, J=7.1 Hz,1H), 6.73-6.54 (m, 4H), 5.06 (dd, J=12.8, 5.3 Hz, 1H), 4.26 (s, 2H),3.80 (s, 6H), 3.64-3.51 (m, 7H), 3.47 (s, 3H), 3.45-3.41 (m, 5H),3.20-3.12 (m, 3H), 2.96-2.83 (m, 1H), 2.61 (s, 1H), 2.27 (s, 6H),2.07-1.97 (m, 1H). LCMS (ESI) m/z: [M+H]+=744.35

Example 55—Preparation of5-(4-[[4-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)piperidin-1-yl]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D28 formic acid)

Using a similar procedure as described in Example 29, step 1 andsubstituting with2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-(piperidin-4-yl)ethyl]piperazin-1-yl]isoindole-1,3-dione(40 mg, 0.088 mmol, 1.00 equiv) in DMF (2 ml) and5-(4-formyl-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamide(34 mg, 0.088 mmol, 1.00 equiv) afforded 5-(4-[[4-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl)piperidin-1-yl]methyl]-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (11.1 mg, 15.3%) as a yellow solid. ¹H NMR (400 MHz,Methanol-d4) δ 8.34 (brs, 2.4H, FA), 7.72 (d, J=8.5 Hz, 1H), 7.58 (s,1H), 7.40 (d, J=1.9 Hz, 1H), 7.27 (d, J=10.4 Hz, 1H), 6.73 (s, 2H), 5.09(dd, J=12.5, 5.4 Hz, 1H), 4.36 (s, 4H), 3.96 (s, 7H), 3.64 (s, 3H),3.57-3.49 (m, 8H), 3.20-3.04 (m, 2H), 2.96-2.82 (m, 2H), 2.78 (s, 4H),2.76-2.67 (m, 6H), 2.67-2.60 (m, 2H), 2.59-2.52 (m, 2H), 2.14 (s, 1H),2.01 (s, 2H), 1.77-1.48 (m, 5H). LCMS (ESI) m/z: [M+H]+=823.45.

Example 56—Preparation of5-(4-((dimethylamino)methyl)-3,5-dimethoxyphenyl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octyl)-7-methyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamideformic acid (Compound D29 formic acid)

Compound D29 was prepared in a similar manner to the preparation ofcompound D21. Compound D29 formic acid (2.4 mg, 4.9%) was obtained as awhite solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.57 (brs, 0.8H, FA), 7.57(s, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.07 (d, J=7.4 Hz, 1H), 6.82 (d, J=7.9Hz, 1H), 6.69 (s, 2H), 5.17 (dd, J=13.3, 5.2 Hz, 1H), 4.36 (s, 2H), 4.29(d, J=3.2 Hz, 2H), 4.18 (s, 2H), 3.92 (s, 6H), 3.64 (s, 3H), 3.53 (t,J=5.8 Hz, 2H), 3.21 (q, J=7.3 Hz, 4H), 2.97-2.80 (m, 2H), 2.73 (s, 6H),2.67-2.60 (m, 2H), 2.49 (dd, J=13.1, 4.8 Hz, 1H), 2.26-2.15 (m, 1H),1.74-1.62 (m, 2H), 1.60-1.50 (m, 2H), 1.49-1.35 (m, 8H). LCMS (ESI) m/z:[M+H]⁺=770.25.

Example 57—Preparation of5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-N-(2-[[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy]ethoxy)ethyl](methyl)amino]ethyl)-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D30 formic acid)

Compound D30 was prepared in a similar manner to the preparation ofcompound D21. Compound D30 formic acid (3 mg, 3.1%) was obtained as anoff-white solid. ¹H NMR (400 MHz, Methanol-d4) δ 8.55 (brs, 2.6H, FA),7.70 (dd, J=8.5, 7.2 Hz, 1H), 7.57 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.36(d, J=7.3 Hz, 1H), 5.10 (dd, J=12.7, 5.5 Hz, 1H), 4.42 (t, J=4.1 Hz,2H), 4.37 (s, 2H), 4.21 (s, 2H), 4.04-3.98 (m, 4H), 3.97 (s, 6H), 3.63(s, 3H), 3.55-3.45 (m, 3H), 3.44-3.35 (m, 3H), 3.26 (s, 2H), 2.93-2.82(m, 1 OH), 2.79-2.65 (m, 2H), 2.63-2.48 (m, 2H), 2.19-2.10 (m, 1H). LCMS(ESI) m/z: [M+H]⁺=802.30.

Example 58—Preparation of5-(4-((4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentanoyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)-3,5-dimethoxyphenyl)-N,7-dimethyl-8-oxo-3,4,7,8-tetrahydro-2,7-naphthyridine-2(1H)-carboxamideformic acid (Compound D31 Formic Acid)

Compound D31 was prepared in a similar manner to the preparation ofcompound D4. Compound D31 formic acid (3.6 mg, 9.4%) was obtained as awhite solid. ¹H NMR (400 MHz, Methanol-d4) δ 8.55 (brs, 0.8H, FA), 7.81(dd, J=8.3, 5.2 Hz, 1H), 7.59 (s, 1H), 7.41 (d, J=2.3 Hz, 1H), 7.33 (dd,J=8.4, 2.2 Hz, 1H), 6.70 (d, J=4.2 Hz, 2H), 5.12 (dd, J=12.6, 5.4 Hz,1H), 4.36 (s, 2H), 4.34-4.26 (m, 2H), 4.24-4.18 (m, 2H), 3.93 (d, J=3.0Hz, 6H), 3.81-3.71 (m, 2H), 3.67-3.59 (m, 5H), 3.57-3.47 (m, 4H),3.30-3.12 (m, 4H), 2.96-2.82 (m, 2H), 2.78 (s, 3H), 2.76-2.72 (m, 1H),2.66-2.47 (m, 4H), 2.19-2.02 (m, 3H), 1.97-1.74 (m, 6H). LCMS (ESI) m/z:[M+H]⁺=882.25.

Example 59—Preparation of5-[4-[(dimethylamino)methyl]-2,5-dimethoxyphenyl]-N-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]ethoxy)ethyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carboxamideformic acid (Compound D32 Formic Acid)

Compound D32 was prepared in a similar manner to the preparation ofcompound D21. Compound D32 formic acid (24.2 mg, 19.5%) was obtained asa green solid. ¹H NMR (400 MHz, Methanol-d4) δ 8.55 (brs, 0.7H, FA),7.51 (d, J=8.3 Hz, 1H), 7.43 (s, 1H), 7.07 (s, 1H), 7.03 (d, J=2.2 Hz,1H), 6.91-6.87 (m, 2H), 5.03 (dd, J=12.6, 5.4 Hz, 1H), 4.33 (s, 2H),4.06-3.93 (m, 2H), 3.86 (s, 3H), 3.73 (s, 6H), 3.61 (s, 6H), 3.45-3.38(m, 4H), 2.90-2.84 (m, 1H), 2.78-2.69 (m, 2H), 2.69-2.47 (m, 8H),2.11-2.04 (m, 1H).LCMS (ESI) m/z: [M+H]+=744.33.

Example 60—Preparation of8-(4-(((2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)ethyl)(methyl)amino)methyl)-3,5-dimethoxyphenyl)-N,N,6-trimethyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2(1H)-carboxamideformic acid (Compound D33 formic acid)

Step 1: Preparation of8-(4-formyl-3,5-dimethoxyphenyl)-N,N,6-trimethyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2(1H)-carboxamide(i-81)

Using a similar procedure as described in Example 23, step 3 andsubstituting with8-bromo-N,N,6-trimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(200 mg, 0.637 mmol, 1.00 equiv) and 4-formyl-3,5-dimethoxyphenylboronicacid (200.5 mg, 0.955 mmol, 1.50 equiv) afforded8-(4-formyl-3,5-dimethoxyphenyl)-N,N,6-trimethyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2(1H)-carboxamide(200.0 mg, 78.7%) as a yellow oil. LCMS (ESI) m/z: [M+H]⁺=400.

Step 2: Preparation of8-(4-(((2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)ethyl)(methyl)amino)methyl)-3,5-dimethoxyphenyl)-N,N,6-trimethyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2(1H)-carboxamideformic acid (Compound D33 formic acid)

Using a similar procedure as described in Example 52, step 3 andsubstituting with8-(4-formyl-3,5-dimethoxyphenyl)-N,N,6-trimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamide(30.0 mg, 0.075 mmol, 1.00 equiv) and2-(2,6-dioxopiperidin-3-yl)-5-(4-[2-[2-(methylamino)ethoxy]ethyl]piperazin-1-yl)isoindole-1,3-dione(33.3 mg, 0.075 mmol, 1.00 equiv) afforded8-[4-([[2-(2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethoxy)ethyl](methyl)amino]methyl)-3,5-dimethoxyphenyl]-N,N,6-trimethyl-5-oxo-3,4-dihydro-1H-2,6-naphthyridine-2-carboxamideformic acid (7.6 mg, 11.2%) as a yellow green solid. ¹H-NMR (400 MHz,Methanol-d4) δ 8.47 (brs, 1.4H, FA), 7.69 (d, J=8.5 Hz, 1H), 7.50 (s,1H), 7.34 (d, J=2.3 Hz, 1H), 7.24 (dd, J=8.6, 2.3 Hz, 1H), 6.77 (s, 2H),5.08 (dd, J=12.4, 5.5 Hz, 1H), 4.50 (s, 2H), 4.09 (s, 2H), 3.97 (s, 6H),3.92-3.87 (m, 2H), 3.76 (t, J=5.2 Hz, 2H), 3.61 (s, 3H), 3.51-3.45 (m,8H), 2.90-2.86 (m, 4H), 2.83 (s, 6H), 2.79-2.71 (m, 1 OH), 2.17-2.07 (m,1H). LCMS (ESI) m/z: [M+H]⁺=827.50.

Example 61—Preparation of(2S,4R)-1-[(2S)-2-(2-[2-[2-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carbonylamino)ethoxy]ethoxy]acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamideformic acid (Compound D34 formic acid)

To a stirred mixture of CDI (9.29 mg, 0.057 mmol, 1.10 equiv) in ACN(0.50 mL) and DMF (0.10 mL) was added(2S,4R)-1-[(2S)-2-[2-[2-(2-aminoethoxy)ethoxy]acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(30 mg, 0.052 mmol, 1.00 equiv) and ACN (0.30 mL) dropwise at roomtemperature under nitrogen atmosphere. After 3 hours,4-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-2-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-1-one(22.35 mg, 0.063 mmol, 1.20 equiv) and TEA (15.82 mg, 0.156 mmol, 3.00equiv) were added. The resulting mixture was stirred at room temperaturefor 12 hours under nitrogen atmosphere. Without any additional work-up,the mixture was purified by Prep-HPLC (conditions: Gemini-NX C18 AXAIPacked, 21.2*150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile PhaseB: ACN; Flow rate: 25 mL/minute; Gradient: 10% B to 25% B in 12 minutes;254/220 nm; RT: 12.30 minutes). This resulted in(2S,4R)-1-[(2S)-2-(2-[2-[2-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carbonylamino)ethoxy]ethoxy]acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamideformic acid (13.9 mg, 26.23%) as a white solid. ¹H NMR (400 MHz,Methanol-d4) δ 8.88 (s, 1H), 8.56 (brs, 1.0H, FA), 7.56 (s, 1H),7.49-7.38 (m, 4H), 6.67 (s, 2H), 4.84-4.75 (m, 2H), 4.67-4.59 (m, 1H),4.52 (s, 1H), 4.48-4.26 (m, 5H), 4.03-3.83 (m, 1 OH), 3.77-3.61 (m, 7H),3.59 (s, 3H), 3.55-3.48 (m, 1H), 3.43-3.34 (m, 2H), 2.84 (s, 6H),2.69-2.52 (m, 2H), 2.48 (s, 3H), 2.31 (dd, J=13.1, 7.7 Hz, 1H),2.18-2.07 (m, 1H), 1.08 (s, 9H). LCMS (ESI) m/z: [M+H]⁺=959.55.

Example 62—Preparation of(2R,4S)-1-[(2R)-2-[2-(2-[2-[2-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carbonylamino)ethoxy]ethoxy]ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(Compound D35)

Compound D35 was prepared in a similar manner to the preparation ofcompound D34. Compound D35 (24.3 mg, 29.8%) was obtained as an off-whitesolid. ¹H NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.59 (s, 1H), 8.17(brs, 0.4H, FA), 7.64 (s, 1H), 7.40 (s, 5H), 6.66 (d, J=18.5 Hz, 3H),5.15 (s, 1H), 4.63-4.53 (m, 1H), 4.51-4.32 (m, 3H), 4.31-4.17 (m, 3H),3.97 (s, 2H), 3.81 (s, 7H), 3.72 (s, 2H), 3.63-3.47 (m, 12H), 3.40 (s,4H), 3.20 (s, 2H), 2.44 (s, 6H), 2.35 (s, 5H), 2.13-2.00 (m, 1H),1.98-1.82 (m, 1H), 0.95 (s, 9H). LCMS (ESI) m/z: [M+H]⁺=1003.60.

Example 63—Preparation of(2S,4R)-1-[(2S)-2-[6-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carbonylamino)hexanamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(Compound D36)

Compound D36 was prepared in a similar manner to the preparation ofcompound D34. Compound D36 formic acid (13.3 mg, 24.6%) was obtained asa white solid. ¹H NMR (400 MHz, DMSO-d6) δ 9.05 (brs, 0.7H, FA), 8.99(s, 1H), 8.56 (t, J=6.0 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.66 (s, 1H),7.41 (q, J=8.2 Hz, 4H), 6.73 (s, 2H), 6.65 (t, J=5.4 Hz, 1H), 6.51 (s,0.3H, FA), 5.12 (d, J=3.6 Hz, 1H), 4.55 (d, J=9.4 Hz, 1H), 4.47-4.39 (m,2H), 4.35 (s, 1H), 4.23 (s, 5H), 3.87 (s, 6H), 3.71-3.62 (m, 2H), 3.51(s, 3H), 3.41 (t, J=5.5 Hz, 2H), 3.30-3.26 (m, 2H), 3.08-2.98 (m, 2H),2.74 (s, 6H), 2.45 (s, 3H), 2.31-2.22 (m, 1H), 2.17-2.00 (m, 2H),1.95-1.87 (m, 1H), 1.55-1.38 (m, 4H), 1.29-1.20 (m, 2H), 0.93 (s, 9H).LCMS (ESI) m/z: [M+H]+=927.55.

Example 64—Preparation of(2S,4R)-1-[(2S)-2-[8-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carbonylamino)octanamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamideformic acid (Compound D37)

Compound D37 was prepared in a similar manner to the preparation ofcompound D34. Compound D37 formic acid (19.9 mg, 37.9%) was obtained asa white solid. ¹H NMR (400 MHz, Methanol-d4) δ 8.89 (s, 1H), 8.57 (brs,0.6H, FA), 7.58 (s, 1H), 7.51-7.40 (m, 4H), 6.69 (s, 2H), 4.66 (s, 1H),4.62-4.49 (m, 3H), 4.38 (d, J=12.6 Hz, 3H), 4.16 (s, 2H), 3.92 (s, 6H),3.90 (s, 1H), 3.82 (dd, J=11.0, 3.9 Hz, 1H), 3.64 (s, 3H), 3.53 (t,J=5.5 Hz, 2H), 3.20 (t, J=7.1 Hz, 2H), 2.71 (s, 6H), 2.63 (t, J=5.2 Hz,2H), 2.49 (s, 3H), 2.36-2.19 (m, 3H), 2.15-2.05 (m, 1H), 1.63 (t, J=6.8Hz, 2H), 1.54 (t, J=7.0 Hz, 2H), 1.36 (s, 6H), 1.05 (s, 9H). LCMS (ESI)m/z: [M+H]+=955.55.

Example 65—Preparation of(2S,4R)-1-[(2S)-2-[10-(5-[4-[(dimethylamino)methyl]-3,5-dimethoxyphenyl]-7-methyl-8-oxo-3,4-dihydro-1H-2,7-naphthyridine-2-carbonylamino)decanamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(Compound D38)

Compound D35 was prepared in a similar manner to the preparation ofcompound D34. Compound D35 formic acid (15.3 mg, 29.6%) was obtained asa white solid. ¹H NMR (400 MHz, Methanol-d4) δ 8.90 (s, 1H), 8.57 (brs,0.5H, FA), 7.59 (s, 1H), 7.52-7.41 (m, 4H), 6.69 (s, 2H), 4.65 (s, 1H),4.62-4.49 (m, 3H), 4.40-4.34 (m, 3H), 4.14 (s, 2H), 3.92 (s, 7H), 3.82(dd, J=10.9, 3.9 Hz, 1H), 3.64 (s, 3H), 3.54 (t, J=5.6 Hz, 2H), 3.20 (t,J=7.2 Hz, 2H), 2.69 (s, 6H), 2.63 (t, J=5.1 Hz, 2H), 2.49 (s, 3H),2.37-2.19 (m, 3H), 2.14-2.05 (m, 1H), 1.68-1.48 (m, 4H), 1.34 (s, 1 OH),1.05 (s, 9H). LCMS (ESI) m/z: [M+H]⁺=983.65.

Example 66—Preparation of Compounds D39-D302 and DD1

In analogy to the procedures described in the examples above, compoundsD39-D302 and DD1 were prepared using the appropriate starting materials

Compound No. LCMS ¹H NMR D39 LCMS (ESI) ¹H NMR (400 MHz, Methanol-d4) δ8.39 (s, 2H, FA), 7.66-7.61 (m, m/z: [M + H]+ = 1H), 7.59 (s, 1H), 7.09(d, J = 7.9 Hz, 2H), 6.72 (s, 2H), 5.11 (dd, J = 795.6 13.3, 5.2 Hz,1H), 4.40 (d, J = 6.8 Hz, 2H), 4.35 (d, J = 7.5 Hz, 4H), 3.95 (s, 8H),3.64 (s, 3H), 3.55 (t, J = 5.6 Hz, 2H), 3.32-3.17 (m, 4H), 2.99-2.69 (m,11H), 2.69-2.60 (m, 2H), 2.49 (td, J = 13.1, 4.8 Hz, 1H), 2.41 (d, J =7.0 Hz, 2H), 2.16 (dtd, J = 12.8, 5.3, 2.4 Hz, 1H), 1.91 (d, J = 13.4Hz, 2H), 1.84 (d, J = 3.6 Hz, 1H), 1.40-1.26 (m, 2H). D40 LCMS (ESI) ¹HNMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H, FA), 7.58 (s, 1H), 7.45 m/z:[M + H]+ = (d, J = 8.4 Hz, 1H), 7.38-7.29 (m, 2H), 6.70 (s, 2H), 5.15(dd, J = 795.6 13.3, 5.1 Hz, 1H), 4.48-4.39 (m, 2H), 4.36 (s, 2H), 4.23(s, 2H), 3.93 (s, 6H), 3.82-3.74 (m, 2H), 3.64 (s, 3H), 3.55 (t, J = 5.6Hz, 2H), 3.18 (s, 4H), 2.92 (ddd, J = 18.3, 13.5, 5.4 Hz, 2H), 2.86-2.59(m, 11H), 2.49 (td, J = 13.2, 4.7 Hz, 1H), 2.40 (d, J = 7.1 Hz, 2H),2.19 (ddd, J = 10.0, 5.2, 2.6 Hz, 1H), 1.93 (d, J = 13.0 Hz, 2H), 1.77(s, 1H), 1.45- 1.33 (m, 2H). D41 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ11.09 (s, 1H), 7.70-7.64 (m, 2H), m/z: [M + H]+ = 7.33 (d, J = 2.3 Hz,1H), 7.29-7.22 (m, 1H), 6.69 (s, 2H), 6.58 (d, J = 837.5 5.0 Hz, 1H),5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.62-4.46 (m, 2H), 4.07 (d, J = 13.0Hz, 3H), 3.89-3.80 (m, 1H), 3.85 (s, 6H), 3.60-3.30 (m, 9H), 3.14-2.82(m, 8H), 2.78 (d, J = 4.8 Hz, 1H), 2.63-2.52 (m, 5H), 2.17 (d, J = 17.0Hz, 1H), 2.06-1.98 (m, 1H), 1.76 (d, J = 12.7 Hz, 2H), 1.60-1.52 (m,3H), 1.27-1.13 (m, 2H), 0.86 (d, J = 6.7 Hz, 3H). D42 LCMS (ESI) ¹H NMR(400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.14 (s, 0H), 7.64 (d, m/z: [M + H]+= J = 9.1 Hz, 2H), 7.31 (d, J = 2.2 Hz, 1H), 7.27-7.18 (m, 1H), 6.60 (d,851.75 J = 5.7 Hz, 3H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.21 (s, 2H),4.05 (d, J J = 12.6 Hz, 2H), 3.79 (s, 6H), 3.66-3.46 (m, 5H), 3.41 (dd,J = 8.1, 2.8 Hz, 2H), 3.31 (s, 4H), 3.00-2.90 (m, 4H), 2.92-2.81 (m,3H), 2.63-2.55 (m, 4H), 2.09-1.94 (m, 3H), 1.76 (d, J = 12.5 Hz, 2H),1.63-1.33 (m, 3H), 1.30-1.13 (m, 3H), 1.10-0.95 (m, 6H). D43 LCMS (ESI)¹H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.16 (s, FA, 1H), 7.67- m/z:[M + H]+ = 7.62 (m, 2H), 7.30 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 8.8,2.3 Hz, 1H), 867.35 6.71 (t, J = 5.5 Hz, 1H), 6.59 (s, 2H), 5.07 (dd, J= 12.9, 5.4 Hz, 1H), 4.22 (s, 2H), 4.03 (d, J = 13.0 Hz, 2H), 3.78 (s,6H), 3.53 (s, 2H), 3.50 (s, 3H), 3.45-3.31 (m, 8H), 3.24 (s, 3H),3.24-3.16 (m, 2H), 2.98- 2.82 (m, 3H), 2.63-2.53 (m, 2H), 2.43 (s, 5H),2.35-2.30 (m, 3H), 2.04-1.97 (m, 1H), 1.74 (d, J = 12.7 Hz, 2H), 1.57(s, 1H), 1.40-1.37 (m, 2H), 1.23-1.10 (m, 2H). D44 LCMS (ESI) ¹H NMR(400 MHz, MeOD) δ 8.49 (s, 2FA, 2H), 7.82 (d, J = 8.3 Hz, m/z: [M + H]+= 1H), 7.58 (s, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.3, 2.3Hz, 867.75 1H), 6.72 (s, 2H), 5.13 (dd, J = 12.6, 5.5 Hz, 1H), 4.38-4.30(m, 3H), 3.95 (s, 5H), 3.90-3.81 (m, 1H), 3.80-3.62 (m, 1H), 3.58-3.50(m, 3H), 3.52-3.45 (m, 1H), 3.15-3.04 (m, 2H), 2.78 (s, 4H), 2.77-2.74(m, 1H), 2.73-2.68 (m, 1H), 2.67-2.57 (m, 3H), 2.56-2.50 (m, 4H),2.25-2.09 (m, 1H), 2.09-1.97 (m, 6H), 1.88-1.79 (m, 4H), 1.58- 1.53 (m,2H), 1.38-1.29 (m, 3H). D45 LCMS (ESI) ¹H NMR (400 MHz, MeOD) δ 8.49 (s,2FA, 2H), 7.82 (d, J = 8.3 Hz, m/z: [M + H]+ = 1H), 7.58 (s, 1H), 7.29(d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.3, 2.3 Hz, 826.35 1H), 6.72 (s,2H), 5.13 (dd, J = 12.6, 5.5 Hz, 1H), 4.38-4.30 (m, 3H), 3.95 (s, 5H),3.90-3.81 (m, 1H), 3.80-3.62 (m, 1H), 3.58-3.50 (m, 3H), 3.52-3.45 (m,1H), 3.15-3.04 (m, 2H), 2.78 (s, 4H), 2.77-2.74 (m, 1H), 2.73-2.68 (m,1H), 2.67-2.57 (m, 3H), 2.56-2.50 (m, 4H), 2.25-2.09 (m, 1H), 2.09-1.97(m, 6H), 1.88-1.79 (m, 4H), 1.58- 1.53 (m, 2H), 1.38-1.29 (m, 3H). D46LCMS (ESI) ¹H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 8.20 (s, FA, 1H),7.68- m/z: [M + H]+ = 7.61 (m, 2H), 7.30 (d, J = 2.2 Hz, 1H), 7.22 (dd,J = 8.7, 2.3 Hz, 1H), 873.75 7.13 (t, J = 5.7, 5.7 Hz, 1H), 6.59 (s,2H), 6.15-5.81 (m, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.26 (s, 2H),4.03 (d, J = 12.9 Hz, 2H), 3.78 (s, 6H), 3.55-3.48 (m, 5H), 3.47-3.36(m, 5H), 2.99-2.83 (m, 3H), 2.63-2.52 (m, 4H), 2.44-2.38 (m, 5H),2.35-2.26 (m, 4H), 2.04- 1.97 (m, 1H), 1.78-1.70 (m, 2H), 1.65-1.47 (m,1H), 1.40-1.32 (m, 2H), 1.26-1.11 (m, 2H). D47 LCMS (ESI) ¹H NMR (400MHz, MeOD) δ 8.51 (s, 1H), 7.81 (d, J = 8.2 Hz, 1H), m/z: [M + H]+ =7.58 (s, 1H), 7.32-7.20 (m, 2H), 6.72 (s, 2H), 5.12 (dd, J = 12.6, 5.4867.55 Hz, 1H), 4.41-4.31 (m, 4H), 3.95 (s, 6H), 3.64 (s, 3H), 3.59-3.45(m, 5H), 3.11-3.07 (m, 2H), 2.92-2.82 (m, 1H), 2.81-2.69 (m, 5H),2.67-2.59 (m, 3H), 2.53-2.57 (m, 4H), 2.20-2.09 (m, 1H), 2.08- 1.96 (m,5H), 1.87-1.78 (m, 4H), 1.68-1.43 (m, 2H). D48 LCMS (ESI) ¹H NMR (400MHz, MeOD) δ 7.68 (d, J = 8.5 Hz, 1H), 7.57 (s, 1H), m/z: [M + H]+ =7.36 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 8.6, 2.3 Hz, 1H), 6.73 (s, 2H),826.55 5.08 (dd, J = 12.5, 5.5 Hz, 1H), 4.48-4.43 (m, 2H), 4.36 (s, 2H),4.07 (d, J = 13.1 Hz, 2H), 3.94 (s, 6H), 3.64 (s, 4H), 3.58-3.50 (m,9H), 3.22-3.17 (m, 2H), 3.01 (t, J = 12.4, 12.4 Hz, 2H), 2.93-2.83 (m,1H), 2.80-2.70 (m, 2H), 2.69-2.59 (m, 2H), 2.18-2.06 (m, 1), 1.88 (d, J= 12.9 Hz, 2H), 1.74-1.68 (m, 3H), 1.44-1.34 (m, 2H). D49 LCMS (ESI) ¹HNMR (400 MHz, Methanol-d4)6 7.61-7.50 (m, 2H), 7.18 (d, J = m/z: [M +H]+ = 8.3 Hz, 1H), 6.73 (s, 2H), 5.13 (dd, J = 13.3, 5.2 Hz, 1H),4.54-4.45 839.31 (m, 2H), 4.38-4.34 (m, 4H), 3.95 (s, 9H), 3.65-3.61 (m,4H), 3.59- 3.51 (m, 4H), 3.37-3.32 (m, 2H), 3.18-3.08 (m, 2H), 3.04-2.98(m, 4H), 2.96-2.86 (m, 1H), 2.86-2.80 (m, 2H), 2.79-2.74 (m, 5H), 2.64(t, J = 5.7 Hz, 2H), 2.59-2.44 (m, 1H), 2.25-2.11 (m, 1H), 2.07- 1.95(m, 2H), 1.80-1.47 (m, 5H). LCMS (ESI) ¹H NMR (400 MHz, Methanol-d4) δ7.56 (s, 1H), 6.77-6.64 (m, 3H), D50 m/z: [M + H]+ = 6.57 (s, 1H), 5.04(dd, J = 13.2, 5.4 Hz, 1H), 4.48-4.28 (m, 6H), 4.17- 839.35 3.98 (m,2H), 3.98-3.86 (m, 10H), 3.76-3.45 (m, 10H), 3.28- 3.20 (m, 3H),3.16-3.01 (m, 2H), 2.94-2.81 (m, 1H), 2.81-2.71 (m, 4H), 2.66-2.56 (m,2H), 2.43 (qd, J = 13.0, 4.7 Hz, 1H), 2.19- 2.07 (m, 1H), 2.06-1.87 (m,3H), 1.86-1.69 (m, 3H), 1.67-1.48 (m, 2H). D51 LCMS (ESI) ¹H NMR (400MHz, Methanol-d4) δ 7.66-7.52 (m, 2H), 6.72 (s, 2H), m/z: [M + H]+ =6.57 (d, J = 8.1 Hz, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.70-4.09821.40 (m, 10H), 3.96 (s, 6H), 3.91-3.73 (m, 4H), 3.64 (s, 3H), 3.55 (t,J = 5.6 Hz, 2H), 3.34 (s, 4H), 3.25-3.10 (m, 1H), 3.08-3.00 (m, 1H),2.98-2.84 (m, 1H), 2.84-2.72 (m, 4H), 2.62 (t, J = 5.3 Hz, 2H), 2.58-2.40 (m, 1H), 2.35-2.06 (m, 5H), 1.38 (d, J = 6.4 Hz, 3H). D52 LCMS(ESI) ¹H NMR (400 MHz, Methanol-d4) δ 7.57 (s, 1H), 7.42 (d, J = 8.2 Hz,m/z: [M + H]+ = 1H), 6.88 (d, J = 2.3 Hz, 1H), 6.80 (dd, J = 8.2, 2.3Hz, 1H), 6.73 (s, 821.55 2H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.60-4.45(m, 2H), 4.43-4.31 (m, 5H), 4.31-4.10 (m, 3H), 3.97 (s, 6H), 3.89-3.70(m, 5H), 3.64 (s, 3H), 3.55 (t, J = 5.6 Hz, 2H), 3.32 (s, 4H), 3.17-3.00(m, 1H), 2.99- 2.85 (m, 1H), 2.85-2.80 (m, 1H), 2.78 (s, 3H), 2.62 (t, J= 5.5 Hz, 2H), 2.57-2.42 (m, 1H), 2.39-2.05 (m, 5H), 1.39 (d, J = 6.6Hz, 3H). D53 LCMS (ESI) ¹H NMR (400 MHz, Methanol-d4) δ 7.58 (s, 1H),7.53 (dd, J = 8.4, 2.0 m/z: [M + H]+ = Hz, 1H), 7.24 (dd, J = 8.4, 2.4Hz, 1H), 7.13 (dd, J = 8.1, 2.3 Hz, 1H), 698.50 6.73 (d, J = 6.8 Hz,2H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (s, 1H), 4.57-4.46 (m, 3H),4.46-4.33 (m, 5H), 4.33-4.26 (m, 1H), 4.23- 4.14 (m, 1H), 3.97 (s, 2H),3.91 (s, 4H), 3.64 (s, 3H), 3.54 (t, J = 5.5 Hz, 2H), 2.98 (d, J = 2.8Hz, 3H), 2.98-2.86 (m, 1H), 2.82 (dd, J = 4.8, 2.5 Hz, 1H), 2.78 (s,3H), 2.62 (s, 2H), 2.51 (qd, J = 13.2, 4.7 Hz, 1H), 2.19 (ddd, J = 10.6,5.3, 2.9 Hz, 1H). D54 LCMS (ESI) ¹H NMR (300 MHz, Methanol-d4) δ 8.46(s, 2H, FA), 7.68-7.56 (m, m/z: [M + H]+ = 2H), 7.07 (d, J = 9.3 Hz,1H), 6.75-6.65 (m, 3H), 4.37 (s, 4H), 3.96 (s, 835.25 7H), 3.65 (s, 3H),3.60-3.50 (m, 4H), 3.50-3.40 (m, 4H), 3.20-3.10 (m, 2H), 2.80-2.50 (m,13H), 2.10-1.90 (m, 3H), 1.80-1.40 (m, 10H). D55 LCMS (ESI) ¹H NMR (300MHz, DMSO-d6) δ 10.96 (s, 1H), 7.66 (s, 1H), 7.52 (d, m/z: [M + H]+ = J= 8.7 Hz, 1H), 7.15-6.99 (m, 4H), 6.62 (s, 1H), 5.15-4.98 (m, 1H),813.35 4.40-4.13 (m, 4H), 3.99-3.72 (m, 7H), 3.61-3.31 (m, 7H), 3.23-2.94 (m, 5H), 2.95-2.69 (m, 3H), 2.66-2.56 (m, 4H), 2.45-2.22 (m, 6H),2.05-1.88 (m, 1H), 1.75 (d, J = 12.3 Hz, 2H), 1.67-1.46 (m, 3H),1.37-1.11 (m, 2H). D56 LCMS (ESI) ¹H NMR (300 MHz, MeOD) δ 8.45 (s, 2FA,2H), 7.60 (d, J = 9.4 Hz, m/z: [M + H]+ = 2H), 6.73 (s, 2H), 6.55 (d, J= 7.4 Hz, 2H), 5.10 (dd, J = 13.2, 5.1 Hz, 835.85 1H), 4.37 (d, J = 4.4Hz, 6H), 3.95 (s, 6H), 3.74 (s, 4H), 3.64 (s, 3H), 3.55 (t, J = 5.2, 5.2Hz, 4H), 3.20-3.06 (m, 2H), 2.97-2.77 (m, 1H), 2.81-2.75 (m, 5H),2.73-2.59 (m, 5H), 2.51-2.45 (m, 3H), 2.23- 1.88 (m, 8H), 1.56 (s, 2H).D57 LCMS (ESI) ¹H NMR (400 MHz, Methanol-d4) δ 7.58 (s, 1H), 7.35 (dd, J= 10.1, m/z: [M + H]+ = 2.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.22 (dd,J = 10.1, 4.0 Hz, 1H), 811.30 6.77-6.71 (m, 2H), 5.36 (dd, J = 12.6, 5.3Hz, 1H), 4.37 (d, J = 6.9 Hz, 4H), 4.04-3.87 (m, 6H), 3.65 (d, J = 6.4Hz, 5H), 3.60-3.52 (m, 4H), 3.36-3.43 (m, 2H), 3.28 (d, J = 10.1 Hz,3H), 3.18-3.05 (m, 2H), 2.93 (d, J = 5.0 Hz, 1H), 2.90 (d, J = 5.2 Hz,1H), 2.86 (d, J = 4.0 Hz, 1H), 2.80-2.84 (m, 1H), 2.79 (s, 3H), 2.70(dd, J = 13.0, 4.7 Hz, 1H), 2.63 (s, 3H), 2.33 (t, J = 5.0 Hz, 1H), 2.02(t, J = 15.9 Hz, 3H), 1.80 (t, J = 8.2 Hz, 2H), 1.65-1.48 (m, 2H). D58825.5 ¹H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.14 (s, 1H, FA), 7.89(q, J = 4.2 Hz, 1H), 7.69 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.13-7.03(m, 2H), 6.73 (s, 2H), 5.06 (dd, J = 13.2, 5.1 Hz, 1H), 4.59 (s, 2H),4.34 (d, J = 17.0 Hz, 1H), 4.21 (d, J = 17.0 Hz, 1H), 4.16 (s, 2H), 3.93(t, J = 5.5 Hz, 2H), 3.87 (s, 6H), 3.53 (s, 3H), 3.48-3.40 (m, 6H),3.01- 2.84 (m, 6H), 2.69-2.55 (m, 7H), 2.47-2.30 (m, 3H), 2.01-1.92 (m,1H), 1.84 (d, J = 13.0 Hz, 2H), 1.68-1.29 (m, 5H). D59 LCMS (ESI) ¹H NMR(300 MHz, Methanol-d4) δ 8.44 (s, 3H, FA), 7.59 (s, 1H), 7.40 m/z: [M +H]+ = (d, J = 8.2 Hz, 1H), 6.88-6.69 (m, 4H), 5.21-5.04 (m, 2H), 4.43-821.55 4.34 (m, 4H), 4.10-3.87 (m, 9H), 3.76-3.61 (m, 8H), 3.56 (s, 2H),3.19-3.05 (m, 1H), 2.96-2.83 (m, 1H), 2.79 (s, 3H), 2.77-2.71 (m, 3H),2.68-2.46 (m, 7H), 2.20 (s, 1H), 1.91 (s, 4H), 1.55 (d, J = 6.6 Hz, 3H).D60 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.14 (s, 1H,FA), 7.65 m/z: [M + H]+ = (s, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 6.65-6.57(m, 3H), 5.19 (dd, J = 633.30 11.6, 4.5 Hz, 1H), 4.22 (s, 2H), 3.81 (s,6H), 3.67 (s, 2H), 3.50 (s, 3H), 3.43-3.31 (m, 6H), 2.96-2.70 (m, 6H),2.67-2.56 (m, 6H), 2.19- 2.11 (m, 1H). D61 LCMS (ESI) ¹H NMR (400 MHz,DMSO-d6) δ 7.79 (d, J = 7.6 Hz, 1H), 7.62 (s, 1H), m/z: [M + H]+ =6.75-6.63 (m, 3H), 6.28 (d, J = 1.6 Hz, 1H), 5.23 (dd, J = 12.5, 5.3 Hz,700.25 1H), 4.31 (s, 2H), 4.22 (s, 2H), 3.94-3.87 (m, 2H), 3.87 (s, 6H),3.50 (s, 3H), 3.4-3.36 (m, 4H), 3.32-3.10 (m, 4H), 2.94-2.81 (m, 1H),2.70-2.60 (m, 1H), 2.59 (s, 3H), 2.58-2.50 (m, 2H), 2.49-2.42 (m, 1H),2.22-2.08 (m, 1H). D62 LCMS (ESI) ¹H NMR (400 MHz, Methanol-d4) δ 8.54(s, 0.3H, FA), 7.56 (s, 1H), m/z: [M + H]+ = 6.62 (s, 2H), 5.05 (dd, J =12.6, 5.3 Hz, 1H), 4.37 (s, 2H), 3.88 (s, 6H), 664.40 3.84 (s, 2H), 3.64(s, 3H), 3.54 (t, J = 5.6 Hz, 2H), 3.23 (s, 3H), 3.18 (d, J = 5.3 Hz,4H), 2.93-2.72 (m, 9H), 2.65 (t, J = 5.6 Hz, 2H), 2.62- 2.49 (m, 1H),2.25-2.12 (m, 1H). D63 839.7 ¹H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H),8.21 (s, 1H, FA), 7.86 (d, J = 4.4 Hz, 1H), 7.68 (t, J = 4.3 Hz, 2H),7.33 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.7, 2.3 Hz, 1H), 6.61 (s, 2H),5.07 (dd, J = 12.7, 5.4 Hz, 1H), 4.60 (s, 2H), 3.98-3.85 (m, 2H), 3.79(s, 6H), 3.78 (s, 1H), 3.58 (s, 3H), 3.51 (s, 3H), 3.47-3.38 (m, 4H),2.98-2.82 (m, 6H), 2.65- 2.54 (m, 3H), 2.49-2.44 (m, 3H), 2.33 (t, J =7.3 Hz, 2H), 2.19-1.95 (m, 3H), 1.63 (d, J = 12.0 Hz, 2H), 1.48-1.02 (m,5H). D64 824.7 1HNMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.15 (s, 0.4H,FA), 7.74-7.63 (m, 2H), 7.36 (d, J = 2.2 Hz, 1H), 7.28 (dd, J = 8.6, 2.2Hz, 1H), 6.73 (s, 2H), 5.08 (dd, J = 12.7, 5.4 Hz, 1H), 4.29 (s, 2H),4.17 (s, 2H), 3.87 (s, 6H), 3.66 (s, 3H), 3.54-3.44 (m, 11H), 3.07- 2.79(m, 4H), 2.64-2.53 (m, 7H), 2.49-2.40 (m, 2H), 2.09-1.97 (m, 1H), 1.85(d, J = 13.0 Hz, 2H), 1.66-1.53 (m, 1H), 1.45 (s, 4H). D65 LCMS (ESI) ¹HNMR (300 MHz, DMSO-d6) δ 7.73-7.52 (m, 3H), 7.40 (d, J = 2.6 m/z: [M +H]+ = Hz, 1H), 6.71 (d, J = 2.0 Hz, 2H), 5.23 (dd, J = 11.4, 5.7 Hz,1H), 4.20 836.65 (d, J = 8.2 Hz, 4H), 3.94 (s, 2H), 3.86 (s, 6H),3.67-3.62 (m, 1H), 3.51 (s, 4H), 3.45-3.30 (m, 4H), 3.28-3.08 (m, 6H),3.07-2.92 (m, 3H), 2.93-2.75 (m, 1H), 2.68-2.55 (m, 9H), 2.23-2.08 (m,1H), 1.92-1.70 (m, 3H), 1.68-1.52 (m, 2H), 1.52-1.28 (m, 2H). D66 752.31H NMR (300 MHz, Methanol-d4) δ 7.41 (d, J = 8.2 Hz, 1H), 7.23 (s, 1H),6.88 (d, J = 2.2 Hz, 1H), 6.86 (s, 2H), 6.80 (dd, J = 8.2, 2.3 Hz, 1H),5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.48 (s, 2H), 4.35 (dd, J = 27.7, 5.0Hz, 6H), 4.13 (d, J = 10.3 Hz, 2H), 3.96 (s, 6H), 3.77 (d, J = 17.5 Hz,4H), 3.63 (s, 3H), 3.49 (dd, J = 10.8, 6.4 Hz, 7H), 3.10 (d, J = 1.7 Hz,2H), 2.99-2.84 (m, 1H), 2.79 (dd, J = 13.0, 2.7 Hz, 1H), 2.60- 2.41 (m,1H), 2.32-2.02 (m, 4H). D67 706.52 ¹H NMR (400 MHz, DMSO-d6) δ 10.81 (s,1H), 8.17 (s, 2H), 7.60 (s, 1H), 6.56 (s, 3H), 5.73 (s, 1H), 4.19 (s,2H), 3.76 (s, 6H), 3.51 (s, 2H), 3.47 (s, 3H), 3.38 (t, J = 5.5 Hz, 2H),3.26-3.08 (m, 1H), 3.07-2.92 (m, 2H), 2.81 (d, J = 11.5 Hz, 2H), 2.57(d, J = 4.2 Hz, 3H), 2.28 (t, J = 7.4 Hz, 3H), 2.04 (s, 1H), 1.57 (d, J= 12.0 Hz, 2H), 1.15 (s, 3H), 1.05 (d, J = 11.4 Hz, 2H). D68 LCMS (ESI)¹H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.23 (s, 2H, FA), 7.69- m/z:7.62 (m, 2H), 7.49 (s, 1H), 7.40 (d, J = 7.9 Hz, 1H), 6.61 (s, 3H), [M +H]+ = 808.43. 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.46-4.26 (m, 3H), 4.22(s, 2H), 3.80 (s, 6H), 3.64 (s, 2H), 3.50 (s, 3H), 3.44-3.36 (m, 2H),3.05 (d, J = 10.6 Hz, 2H), 2.92 (d, J = 10.4 Hz, 3H), 2.67-2.57 (m, 5H),2.49- 2.30 (m, 3H), 2.29-2.06 (m, 4H), 2.04-1.94 (m, 1H), 1.87-1.57 (m,6H), 1.40 (s, 2H), 1.34-1.07 (m, 3H). D69 LCMS (ESI) ¹H NMR (400 MHz,Methanol-d4) δ 7.67-7.48 (m, 2H), 7.45-7.32 m/z: [M + H]+ = (m, 2H),6.73 (d, J = 6.3 Hz, 2H), 5.25-5.09 (m, 1H), 4.52-4.42 (m, 809.40 2H),4.37 (d, J = 3.6 Hz, 3H), 3.96 (s, 2H), 3.95 (s, 6H), 3.75 (d, J = 13.9Hz, 2H), 3.64 (s, 3H), 3.60 (d, J = 12.7 Hz, 2H), 3.54 (d, J = 5.6 Hz,2H), 3.32-3.25 (m, 3H), 3.19 (s, 1H), 3.18-3.05 (m, 2H), 2.98- 2.86 (m,1H), 2.82 (dd, J = 4.8, 2.5 Hz, 1H), 2.78 (s, 3H), 2.64 (t, J = 5.6 Hz,2H), 2.51 (qd, J = 13.2, 4.7 Hz, 1H), 2.24-2.14 (m, 1H), 2.04 (d, J =13.9 Hz, 2H), 2.00-1.86 (m, 1H), 1.86-1.70 (m, 3H), 1.68- 1.51 (m, 2H).D70 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 8.15 (s, 1H, FA), 7.73 (d, J= 8.5 Hz, m/z: 1H), 7.66-7.49 (m, 3H), 7.38 (d, J = 2.2 Hz, 1H),7.33-7.23 (m, 2H), [M + H]+ = 824.35. 6.62-6.54 (m, 3H), 4.22 (s, 2H),4.07 (d, J = 13.1 Hz, 2H), 3.78 (s, 6H), 3.55-3.49 (m, 5H), 3.44-3.39(m, 4H), 2.97 (t, J = 12.5 Hz, 3H), 2.60 (d, J = 4.2 Hz, 4H), 2.44-2.31(m, 8H), 1.76 (d, J = 12.9 Hz, 2H), 1.65-1.52 (m, 1H), 1.42-1.30 (m,2H), 1.25-1.13 (m, 2H). D71 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ7.86-7.52 (m, 4H), 6.73 (s, 2H), m/z: 5.10 (dd, J = 13.2, 5.2 Hz, 1H),4.51-4.28 (m, 2H), 4.24 (d, J = 9.8 [M + H]+ = 809.43. Hz, 4H), 3.88 (s,6H), 3.67-3.58 (m, 2H), 3.51 (s, 3H), 3.43-3.28 (m, 6H), 3.22-2.99 (m,6H), 2.96-2.72 (m, 4H), 2.67-2.53 (m, 8H), 2.48-2.33 (m, 2H), 2.10-1.95(m, 4H). D72 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 7.73 (d, J = 7.9 Hz,1H), 7.62 (s, 1H), m/z: 7.53-7.41 (m, 2H), 6.73 (s, 2H), 5.10 (dd, J =13.2, 5.1 Hz, 1H), 4.50- [M + H]+ = 809.43. 4.29 (m, 2H), 4.24 (d, J =10.0 Hz, 4H), 3.87 (s, 6H), 3.67-3.54 (m, 5H), 3.44-3.28 (m, 6H),3.19-2.86 (m, 8H), 2.79-2.72 (m, 2H), 2.67-2.52 (m, 8H), 2.47-2.31 (m,2H), 2.06-1.95 (m, 4H). D73 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.1(br s, 1H), 8.26 (s, 2H, FA), m/z: [M + H]+ = 7.64 (s, 1H), 7.55 (d, J =8.9 Hz, 3H), 6.61 (s, 3H), 5.11 (dd, J = 13.2, 808.43 5.1 Hz, 1H), 4.42(d, J = 17.1 Hz, 1H), 4.28 (d, J = 17.2 Hz, 1H), 4.22 (s, 2H), 3.80 (s,6H), 3.62 (s, 2H), 3.50 (s, 3H), 3.40 (t, J = 5.9 Hz, 2H), 3.05 (d, J =10.7 Hz, 2H), 2.90 (d, J = 12.0 Hz, 3H), 2.71-2.54 (m, 5H), 2.42 (s,4H), 2.46-2.35 (m, 3H), 2.16 (q, J = 12.1 Hz, 4H), 2.05-1.93 (m, 1H),1.82-1.58 (m, 6H), 1.41 (s, 2H), 1.32-1.12 (m, 3H). D74 LCMS (ESI) ¹HNMR (300 MHz, DMSO-d6) δ 8.15 (s, 1H, FA), 7.64 (s, 1H), 6.68 m/z: (s,2H), 6.64-6.57 (m, 1H), 4.22 (s, 2H), 3.95 (s, 2H), 3.84 (s, 6H), [M +H]+ = 701.50. 3.51 (s, 4H), 3.44-3.39 (m, 5H), 3.19-3.08 (m, 3H), 2.86(s, 4H), 2.70-2.57 (m, 7H), 2.46-2.41 (m, 2H), 2.10 (s, 3H), 1.74 (s,7H), 1.67-1.55 (m, 6H), 1.45-1.26 (m, 5H). D75 LCMS (ESI) ¹H NMR (400MHz, Methanol-d4) δ 8.22 (s, 1H, FA), 7.58 (s, 1H), 7.38 m/z: (d, J =6.1 Hz, 1H), 6.73 (s, 2H), 5.12 (dd, J = 12.7, 5.4 Hz, 1H), 4.36 [M +H]+ = 859.50. (s, 4H), 3.95 (s, 6H), 3.64 (s, 3H), 3.55 (t, J = 5.6 Hz,4H), 3.50 (t, J = 4.7 Hz, 4H), 3.18-3.06 (m, 2H), 2.98 (s, 4H),2.90-2.69 (m, 8H), 2.64 (t, J = 5.7 Hz, 2H), 2.19-2.11 (m, 1H), 2.02 (d,J = 13.8 Hz, 2H), 1.80-1.46 (m, 5H). D76 LCMS (ESI) ¹H NMR (400 MHz,DMSO-d6) δ 11.07 (s, 1H), 8.19 (s, 2H, FA), 8.09 m/z: (s, 1H), 7.82 (s,1H), 7.63 (s, 1H), 7.42 (d, J = 8.7 Hz, 2H), 6.93 (d, J = [M + H]+ =820.55. 8.7 Hz, 2H), 6.58 (s, 3H), 5.36 (dd, J = 11.9, 5.1 Hz, 1H), 4.21(s, 2H), 3.78 (s, 6H), 3.52 (s, 2H), 3.50 (s, 3H), 3.42-3.39 (m, 6H),3.14- 3.11 (m, 4H), 2.86-2.79 (m, 3H), 2.60 (d, J = 4.3 Hz, 4H), 2.49-2.44 (m, 5H), 2.29-2.22 (m, 1H), 2.08-2.00 (m, 2H), 1.65-1.58 (m, 2H),1.40-1.34 (m, 2H), 1.29-1.22 (m, 1H), 1.18-1.08 (m, 2H). D77 LCMS (ESI)¹H NMR (300 MHz, Methanol-d4) δ 8.41 (s, 1H, FA), 7.72 (d, J = 7.8 m/z:Hz, 1H), 7.58 (s, 1H), 6.73 (s, 3H), 6.17 (s, 1H), 5.27 (dd, J = 12.3,5.3 [M + H]+ = 811.55 Hz, 1H), 4.36 (s, 4H), 3.95 (s, 6H), 3.64 (s, 3H),3.60-3.49 (m, 4H), 3.43 (s, 4H), 3.13-3.04 (m, 1H), 2.92-2.76 (m, 9H),2.72-2.54 (m, 6H), 2.36-2.24 (m, 1H), 2.08-1.95 (m, 2H), 1.78-1.44 (m,5H). D78 LCMS (ESI) ¹H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 2H, FA),7.58 (s, 1H), 7.51 m/z: [M + H]+ = (d, J = 9.6 Hz, 1H), 6.73 (s, 2H),5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.36 858.50 (s, 4H), 3.96 (s, 6H), 3.64(s, 4H), 3.55 (t, J = 5.6 Hz, 3H), 3.44 (s, 4H), 3.14-3.07 (m, 1H),2.97-2.83 (m, 2H), 2.78 (s, 4H), 2.76- 2.69 (m, 5H), 2.66-2.57 (m, 4H),2.17-2.11 (m, 1H), 2.06-1.98 (m, 2H), 1.75-1.49 (m, 5H). D79 793.47 D80826.37 ¹H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.13 (s, 1H), 7.66 (d,J = 8.5 Hz, 1H), 7.61 (s, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.23 (dd, J =8.7, 2.3 Hz, 1H), 6.61 (s, 1H), 4.19 (s, 2H), 3.79 (s, 6H), 3.76 (s,2H), 3.48 (s, 3H), 3.30 (s, 6H), 2.99 (t, J = 10.0 Hz, 2H), 2.57 (d, J =4.1 Hz, 2H), 2.36-2.28 (m, 2H), 1.98 (d, J = 12.8 Hz, 1H), 1.37 (s, 3H),1.80- 1.61 (m, 2H), 1.32-1.18 (m, 2H). D81 LCMS (ESI) ¹H NMR (300 MHz,DMSO-d6) δ 11.08 (s, 1H), 8.15 (s, 2H, FA), 7.69 m/z: (d, J = 8.5 Hz,1H), 7.63 (s, 1H), 7.34 (s, 1H), 7.26 (d, J = 8.8 Hz, 1H), [M + H]+ =849.25. 6.75 (s, 1H), 6.64 (s, 2H), 5.07 (dd, J = 12.9, 5.3 Hz, 1H),4.20 (s, 2H), 3.82 (s, 10H), 3.50 (s, 5H), 3.45-3.41 (m, 8H), 3.05-2.87(m, 4H), 2.63-2.58 (m, 3H), 2.41-2.26 (m, 3H), 2.06-1.95 (m, 1H), 1.79-1.66 (m, 2H), 1.45-1.36 (m, 3H), 1.33-1.21 (m, 2H), 0.57-0.51 (m, 2H),0.45-0.39 (m, 2H). D82 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J= 8.5 Hz, 1H), 7.64 (s, 1H), m/z: [M + H]+ = 7.35 (d, J = 2.2 Hz, 1H),7.27 (d, J = 8.9 Hz, 1H), 6.68-6.56 (m, 3H), 939. 5.72-5.59 (m, 2H),5.27 (dd, J = 13.0, 5.3 Hz, 1H), 4.77 (p, J = 6.2 Hz, 1H), 4.22 (s, 2H),3.82 (s, 8H), 3.50 (s, 3H), 3.47-3.38 (m, 8H), 3.16-2.96 (m, 4H),2.90-2.66 (m, 2H), 2.65-2.53 (m, 7H), 2.40- 2.26 (m, 3H), 2.14-2.03 (m,1H), 1.72 (d, J = 12.3 Hz, 2H), 1.47- 1.35 (m, 3H), 1.31-1.19 (m, 8H).D83 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.16 (s, 2H,FA), 7.64 m/z: (s, 1H), 7.44 (d, J = 11.8 Hz, 1H), 7.29 (d, J = 8.0 Hz,1H), 6.65-6.52 [M + H]+ = 827.45. (m, 3H), 5.09 (dd, J = 13.4, 5.0 Hz,1H), 4.41-4.19 (m, 5H), 3.80 (s, 7H), 3.65 (s, 4H), 3.50 (s, 5H), 3.41(s, 2H), 3.04 (s, 4H), 2.98-2.87 (m, 3H), 2.61-2.58 (m, 4H), 2.44-2.30(m, 4H), 2.07-1.93 (m, 1H), 1.72-1.59 (m, 2H), 1.47-1.10 (m, 6H). D84LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.16 (s, 2H, FA),7.64 m/z: (s, 1H), 7.43 (d, J = 11.6 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H),6.66-6.56 [M + H]+ = 827.35. (m, 3H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H),4.40-4.25 (m, 2H), 4.22 (s, 2H), 3.88-3.74 (m, 9H), 3.50 (s, 4H),3.45-3.38 (m, 5H), 3.11 (s, 4H), 3.06-2.85 (m, 4H), 2.65-2.57 (m, 5H),2.41-2.32 (m, 4H), 2.04-1.93 (m, 1H), 1.71 (d, J = 12.4 Hz, 2H),1.44-1.24 (m, 5H). D85 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 10.95 (s,1H), 8.18 (s, 2H, FA), 7.64 m/z: (s, 1H), 7.55-7.48 (m, 1H), 7.06 (d, J= 7.9 Hz, 2H), 6.65-6.56 (m, [M + H]+ = 809.80. 3H), 5.05 (dd, J = 13.3,5.1 Hz, 1H), 4.33 (d, J = 16.9 Hz, 1H), 4.26- 4.17 (m, 3H), 3.81 (s,6H), 3.71 (s, 2H), 3.50 (s, 3H), 3.41 (t, J = 5.6 Hz, 3H), 3.30-3.24 (m,5H), 3.02-2.85 (m, 4H), 2.63-2.52 (m, 6H), 2.43-2.23 (m, 6H), 2.00-1.92(m, 1H), 1.68 (d, J = 12.5 Hz, 2H), 1.44-1.30 (m, 3H), 1.29-1.16 (m,2H). D86 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.16 (s,1H, FA), 7.64 m/z: (s, 1H), 7.24 (s, 1H), 7.05 (d, J = 13.2 Hz, 1H),6.66 (s, 2H), 6.60 (d, [M + H]+ = 840.40. J = 4.6 Hz, 1H), 5.07 (dd, J =12.8, 5.4 Hz, 1H), 4.22 (s, 2H), 3.87 (s, 2H), 3.83 (s, 6H), 3.53-3.44(m, 8H), 3.43-3.38 (m, 3H), 3.09 (d, J = 11.4 Hz, 2H), 2.94-2.83 (m,1H), 2.63-2.54 (m, 6H), 2.49-2.41 (m, 5H), 2.37-2.30 (m, 2H), 2.06-1.97(m, 1H), 1.73 (d, J = 12.6 Hz, 2H), 1.47-1.36 (m, 3H), 1.35-1.22 (m,2H). D87 LCMS (ESI) .¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.16 (s,1H, FA), 7.67- m/z: 7.61 (m, 2H), 7.37 (t, J = 7.7 Hz, 1H), 6.66-6.55(m, 3H), 5.10 (dd, [M + H]+ = 840.95. J = 12.8, 5.4 Hz, 1H), 4.22 (s,2H), 3.81 (s, 6H), 3.74 (s, 2H), 3.50 (s, 4H), 3.41 (t, J = 5.5 Hz, 5H),3.22 (t, J = 4.8 Hz, 5H), 2.99 (d, J = 11.2 Hz, 2H), 2.94-2.78 (m, 2H),2.64-2.56 (m, 5H), 2.40-2.31 (m, 4H), 2.07-1.97 (m, 1H), 1.69 (d, J =12.5 Hz, 2H), 1.38 (s, 3H), 1.29- 1.16 (m, 2H). D88 LCMS (ESI) ¹H NMR(300 MHz, DMSO-d6, D20) δ 7.80 (d, J = 11.1 Hz, 1H), m/z: 8.14(s, 0H,FA), 7.64 (s, 1H), 7.56 (s, 1H), 6.73 (s, 2H), 5.12 (dd, J = [M + H]+ =841.55. 12.8, 5.4 Hz, 1H), 4.31-4.14 (m, 4H), 3.87 (s, 6H), 3.51 (s,3H), 3.48- 3.39 (m, 6H), 3.31-3.06 (m, 4H), 3.06-2.80 (m, 4H), 2.66-2.56(m, 5H), 2.56-2.53 (m, 4H), 2.10-1.99 (m, 1H), 1.91-1.82 (m, 2H),1.81-1.15 (m, 6H). D89 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.02 (s,1H), 8.27 (s, 1H, FA), 7.67- m/z: 7.55 (m, 1H), 7.28 (t, J = 7.7 Hz,1H), 6.92 (d, J = 7.4 Hz, 1H), 6.73 [M + H]+ = 782.65. (d, J = 8.1 Hz,1H), 6.67-6.62 (m, 1H), 6.59 (s, 2H), 5.56 (t, J = 5.0 Hz, 1H), 5.11(dd, J = 13.2, 5.1 Hz, 1H), 4.27-4.06 (m, 5H), 3.83- 3.73 (m, 7H), 3.65(s, 2H), 3.50 (s, 3H), 3.40 (t, J = 5.4 Hz, 2H), 3.28 (t, J = 7.1 Hz,3H), 3.14-3.00 (m, 4H), 2.97-2.86 (m, 1H), 2.67- 2.53 (m, 2H), 2.34-2.25(m, 1H), 2.09-1.98 (m, 1H), 1.98-1.84 (m, 2H), 1.63-1.50 (m, 2H),1.43-1.21 (m, 10H). D90 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.12 (s,1H), 8.18(s, 0H, FA), 7.83 m/z: (d, J = 8.3 Hz, 1H), 7.64 (s, 1H), 7.43(d, J = 2.2 Hz, 1H), 7.35 (dd, J = [M + H]+ = 755.65. 8.3, 2.3 Hz, 1H),6.69 (t, J = 5.4 Hz, 1H), 6.64 (s, 2H), 5.12 (dd, J = 12.9, 5.3 Hz, 1H),4.19 (dd, J = 13.5, 7.1 Hz, 4H), 3.91 (s, 2H), 3.82 (s, 6H), 3.65-3.55(m, 4H), 3.50 (s, 3H), 3.41 (t, J = 5.3 Hz, 4H), 3.13- 3.04 (m, 2H),2.96-2.83 (m, 1H), 2.66-2.55 (m, 2H), 2.15-2.00 (m, 3H), 1.85-1.68 (m,2H), 1.57-1.37 (m, 4H). D91 LCMS (ESI) ¹H NMR (300 MHz, Methanol-d4) δ8.54 (br s, 1H, FA), 7.72 (d, J = m/z: [M + H]+ = 8.4 Hz, 1H), 7.61 (s,1H), 7.41 (d, J = 2.1 Hz, 1H), 7.28 (d, J = 8.7 Hz, 811.70 1H),6.98-6.87 (m, 2H), 5.10 (dd, J = 12.3, 5.3 Hz, 1H), 4.39-4.33 (m, 4H),3.99 (s, 3H), 3.64 (s, 4H), 3.55 (s, 8H), 3.09 (t, J = 12.1 Hz, 2H),2.92-2.80 (m, 5H), 2.80-2.71 (m, 5H), 2.64 (d, J = 5.9 Hz, 4H), 2.14 (s,1H), 2.00 (s, 1H), 1.78-1.45 (m, 5H). D92 LCMS (ESI) ¹H NMR (300 MHz,DMSO-d6) δ 11.09 (s, 1H), 8.16 (s, 2H, FA), 8.08 m/z: (d, J = 1.7 Hz,1H), 7.73-7.64 (m, 2H), 7.42 (d, J = 1.8 Hz, 1H), 7.34 [M + H]+ =794.80. (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 8.7, 2.3 Hz, 1H), 6.61 (q, J= 4.4 Hz, 1H), 5.08 (dd, J = 12.8, 5.4 Hz, 1H), 4.22 (s, 2H), 3.85 (s,3H), 3.69 (s, 2H), 3.50 (s, 3H), 3.46-3.40 (m, 8H), 2.98-2.83 (m, 3H),2.64- 2.55 (m, 5H), 2.45-2.25 (m, 5H), 2.17 (t, J = 11.4 Hz, 2H), 2.06-1.98 (m, 1H), 1.65 (d, J = 11.8 Hz, 2H), 1.44-1.09 (m, 6H D93 848.51 D94863.63 D95 863.56 ¹H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.14 (s,1H), 7.62 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 2.3 Hz, 1H), 7.20 (dd, J =8.6, 2.4 Hz, 1H), 6.56 (s, 3H), 5.03 (dd, J = 13.0, 5.4 Hz, 1H), 4.19(s, 2H), 4.10-3.91 (m, 3H), 3.76 (s, 6H), 3.51 (s, 2H), 3.47 (s, 3H),3.37 (d, J = 5.8 Hz, 1H), 3.15 (d, J = 2.4 Hz, 2H), 2.92 (t, J = 12.1Hz, 2H), 2.89-2.80 (m, 1H), 2.65 (q, J = 1.9 Hz, 1H), 2.57 (d, J = 4.3Hz, 3H), 2.34-2.23 (m, 4H), 1.99 (d, J = 14.8 Hz, 3H), 1.77-1.67 (m,2H), 1.59 (s, 5H), 1.28 (d, J = 7.0 Hz, 1H), 1.24-1.08 (m, 1H). D96835.56 ¹H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.16 (s, 1H), 7.70-7.49 (m, 2H), 7.28 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.7, 2.4 Hz, 1H),6.55 (s, 2H), 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 4.19 (s, 2H), 4.01 (d, J= 13.0 Hz, 2H), 3.75 (s, 5H), 3.73-3.59 (m, 2H), 3.47 (s, 3H), 3.38 (t,J = 5.5 Hz, 2H), 3.15 (s, 2H), 2.99-2.88 (m, 2H), 2.88-2.79 (m, 1H),2.57 (d, J = 4.3 Hz, 3H), 2.43-2.12 (m, 3H), 2.03-1.93 (m, 1H), 1.74 (d,J = 12.8 Hz, 2H), 1.62 (s, 1H), 1.43 (t, J = 7.1 Hz, 1H), 1.24- 1.12 (m,2H), 0.43 (q, J = 4.8 Hz, 1H), 0.22-0.03 (m, 1H). D97 890.39 D98 865.52D99 837.59 D100 837.59 D101 850.44 D102 851.59 D103 867.5 D104 873.43D105 831.57 D106 LCMS (ESI) ¹H NMR (400 MHz, Methanol-d4) δ 7.56 (s,1H), 6.77-6.64 (m, 3H), m/z: [M + H]+ = 6.57 (s, 1H), 5.04 (dd, J =13.2, 5.4 Hz, 1H), 4.48-4.28 (m, 6H), 4.17- 878.55 3.98 (m, 2H),3.98-3.86 (m, 10H), 3.76-3.45 (m, 10H), 3.28- 3.20 (m, 3H), 3.16-3.01(m, 2H), 2.94-2.81 (m, 1H), 2.81-2.71 (m, 4H), 2.66-2.56 (m, 2H), 2.43(qd, J = 13.0, 4.7 Hz, 1H), 2.19- 2.07 (m, 1H), 2.06-1.87 (m, 3H),1.86-1.69 (m, 3H), 1.67-1.48 (m, 2H). D107 LCMS (ESI) ¹H NMR (300 MHz,Methanol-d4) δ 8.45 (br s, 1H, FA), 7.64 (d, J = m/z: 8.3 Hz, 1H), 7.58(s, 1H), 6.82 (d, J = 2.0 Hz, 1H), 6.73 (s, 2H), 6.66 [M + H]+ = 835.45.(dd, J = 8.3, 2.1 Hz, 1H), 5.07 (dd, J = 12.3, 5.4 Hz, 1H), 4.46 (s,2H), 4.36 (s, 2H), 4.21-4.08 (m, 3H), 3.99-3.85 (m, 7H), 3.78 (s, 4H),3.64 (s, 3H), 3.55 (t, J = 5.4 Hz, 2H), 2.97 (s, 2H), 2.91-2.68 (m, 6H),2.66-2.58 (m, 4H), 2.51-2.41 (m, 2H), 2.19-2.01 (m, 1H), 1.97- 1.75 (m,4H), 0.98 (d, J = 5.0 Hz, 3H). D109 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6)δ 11.07 (s, 1H), 8.19 (s, 1H, FA), 7.64 m/z: (d, J = 8.3 Hz, 2H), 6.77(d, J = 2.1 Hz, 1H), 6.65 (dd, J = 8.4, 2.1 Hz, [M + H]+ = 821.50. 1H),6.62-6.57 (m, 3H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.22 (s, 2H), 3.80(s, 6H), 3.73 (s, 4H), 3.70 (s, 2H), 3.50 (s, 4H), 3.48-3.45 (m, 6H),3.09-3.01 (m, 3H), 2.92-2.87 (m, 1H), 2.60 (d, J = 4.3 Hz, 4H),2.45-2.40 (m, 2H), 2.28 (s, 4H), 2.05-1.97 (m, 1H), 1.78-1.69 (m, 4H).D110 LCMS (ESI) m/z: [M + H]+ = 794.30 D111 LCMS (ESI) ¹H NMR (400 MHz,DMSO-d6) δ 11.06 (s, 1H), 7.60 (s, 1H), 7.55 (d, J = m/z: 8.4 Hz, 1H),7.22-7.14 (m, 2H), 6.98 (dd, J = 8.5, 2.1 Hz, 1H), 6.64 [M + H]+ =643.25. (s, 2H), 6.58 (d, J = 4.6 Hz, 1H), 5.02 (dd, J = 13.0, 5.3 Hz,1H), 4.32 (d, J = 5.3 Hz, 2H), 4.21 (s, 2H), 3.86 (s, 6H), 3.49 (s, 3H),3.41 (d, J = 5.5 Hz, 3H), 2.95-2.81 (m, 1H), 2.59 (d, J = 4.3 Hz, 3H),2.54 (s, 3H), 1.99 (d, J = 12.5 Hz, 1H). D112 LCMS (ESI) ¹H NMR (400MHz, DMSO-d6) δ 11.06 (s, 1H), 7.63 (t, J = 4.3 Hz, m/z: 2H), 7.31 (d, J= 2.4 Hz, 1H), 7.11-7.01 (m, 1H), 6.64 (s, 2H), 6.58 [M + H]+ = 657.10.(d, J = 4.5 Hz, 1H), 5.04 (dd, J = 12.9, 5.3 Hz, 1H), 4.64 (s, 2H), 4.20(s, 2H), 3.85 (s, 6H), 3.48 (s, 3H), 3.09 (s, 3H), 2.86 (d, J = 12.5 Hz,1H), 2.68 (p, J = 1.8 Hz, 3H), 2.59 (s, 3H), 2.58 (s, 6H), 2.00 (d, J =12.5 Hz, 1H). D113 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H),8.18 (s, 1H), 7.86 (d, m/z: [M + H]+ = J = 7.7 Hz, 1H), 7.81-7.74 (m,2H), 7.64 (s, 1H), 6.62 (s, 2H), 6.60- 822.70 6.57 (m, 1H), 5.14 (dd, J= 12.9, 5.4 Hz, 1H), 4.22 (s, 2H), 3.80 (s, 6H), 3.67 (s, 2H), 3.50 (s,4H), 3.41 (t, J = 5.6 Hz, 4H), 3.03 (d, J = 10.9 Hz, 2H), 2.97-2.88 (m,3H), 2.77 (t, J = 12.2 Hz, 1H), 2.63- 2.58 (m, 4H), 2.43-2.36 (m, 2H),2.30-2.21 (m, 2H), 2.12-2.02 (m, 3H), 1.86-1.79 (m, 2H), 1.78-1.63 (m,4H), 1.43-1.28 (m, 3H), 1.25-1.14 (m, 2H). D114 LCMS (ESI) 1HNMR (400MHz, DMSO-d6) δ 11.12 (s, 1H), 9.24 (s, 1H, TFA), 8.32 m/z: (s, 1H,TFA), 7.86 (d, J = 8.2 Hz, 1H), 7.64 (s, 1H), 7.35-7.26 (m, [M + H]+ =892.45. 2H), 6.75 (s, 2H), 6.62 (d, J = 4.6 Hz, 1H), 5.13 (dd, J = 12.8,5.4 Hz, 1H), 5.09-5.00 (m, 1H), 4.27-4.10 (m, 4H), 3.89 (d, J = 2.4 Hz,6H), 3.52 (s, 3H), 3.43-3.41 (m, 4H), 3.24-3.16 (m, 1H), 3.08-2.81 (m,5H), 2.75-2.69 (m, 1H), 2.66-2.52 (m, 8H), 2.43-2.39 (m, 1H), 2.17-1.96(m, 6H), 1.94-1.81 (m, 4H), 1.73-1.61 (m, 2H), 1.24 (s, 6H). D115 LCMS(ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.18 (s, 1H, FA), 7.68m/z: (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.26(dd, J = [M + H]+ = 809.35. 8.8, 2.3 Hz, 1H), 6.64 (s, 2H), 6.59 (q, J =4.4 Hz, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.21 (s, 2H), 3.90 (s,2H), 3.82 (s, 6H), 3.50 (s, 3H), 3.44-3.39 (m, 8H), 3.37-3.28 (m, 5H),3.08 (t, J = 8.9 Hz, 2H), 2.94- 2.80 (m, 3H), 2.62-2.56 (m, 4H), 2.30(t, J = 7.2 Hz, 2H), 2.21- 2.13 (m, 1H), 2.06-1.94 (m, 2H), 1.61-1.49(m, 2H), 1.48-1.39 (m, 1H). D116 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ11.12 (s, 1H), 8.19 (s, 2H, FA), 7.86- m/z: 7.80 (m, 1H), 7.64 (s, 1H),7.30-7.23 (m, 2H), 6.60 (s, 3H), 5.12 [M + H]+ = 699.40. (dd, J = 12.8,5.4 Hz, 1H), 4.94 (t, J = 5.5 Hz, 1H), 4.21 (s, 2H), 3.78 (s, 6H),3.72-3.65 (m, 5H), 3.50 (s, 3H), 3.40 (s, 3H), 3.13-3.08 (m, 2H),2.91-2.86 (m, 1H), 2.63-2.57 (m, 5H), 2.09-2.00 (m, 1H). D117 LCMS (ESI)¹H NMR (300 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.47 (s, 1H, TFA), m/z: 7.93(d, J = 7.7 Hz, 1H), 7.87 (s, 1H), 7.83-7.77 (m, 1H), 7.64 (s, [M + H]+= 823.55. 1H), 6.74 (s, 2H), 6.63 (s, 1H), 5.16 (dd, J = 12.8, 5.4 Hz,1H), 4.24 (d, J = 7.7 Hz, 4H), 3.88 (s, 6H), 3.62 (d, J = 10.7 Hz, 2H),3.52 (s, 3H), 3.44-3.31 (m, 6H), 3.21-3.00 (m, 7H), 2.98-2.72 (m, 4H),2.66- 2.58 (m, 4H), 2.50-2.42 (m, 4H), 2.15-1.93 (m, 5H). D118 LCMS(ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.18 (s, 2H, FA), 7.69m/z: (d, J = 8.5 Hz, 1H), 7.34 (d, J = 2.8 Hz, 2H), 7.26 (dd, J = 8.7,2.2 Hz, [M + H]+ = 849.50. 1H), 6.68-6.56 (m, 3H), 5.08 (dd, J = 12.8,5.3 Hz, 1H), 4.23 (s, 2H), 3.82 (s, 9H), 3.49-3.30 (m, 10H), 3.07 (d, J= 11.1 Hz, 3H), 2.97- 2.73 (m, 3H), 2.63-2.55 (m, 6H), 2.40-2.30 (m,2H), 2.08-1.97 (m, 1H), 1.73 (d, J = 12.2 Hz, 2H), 1.51-1.18 (m, 5H),1.00 (s, 2H), 0.95-0.86 (m, 2H). D119 LCMS (ESI) ¹H NMR (400 MHz,DMSO-d6) δ 11.06 (s, 1H), 8.95 (s, 1H), 7.73- m/z: [M + H]+ = 7.61 (m,2H), 6.94 (d, J = 2.2 Hz, 1H), 6.86 (dd, J = 8.6, 2.1 Hz, 1H), 766.256.74 (s, 2H), 6.70 (d, J = 7.2 Hz, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H),4.28 (s, 2H), 4.22 (s, 2H), 3.88 (s, 7H), 3.59 (t, J = 9.6 Hz, 1H),3.55- 3.48 (m, 5H), 3.45 (t, J = 5.5 Hz, 2H), 3.28-3.23 (m, 1H),2.97-2.82 (m, 2H), 2.75 (s, 6H), 2.71-2.65 (m, 1H), 2.62-2.53 (m, 3H),2.13- 1.94 (m, 3H), 1.71-1.59 (m, 1H), 1.55-1.41 (m, 1H). D120 LCMS(ESI) m/z: [M + H]+ = 810.20 D121 LCMS (ESI) m/z: [M + H]+ = 810.45 D122LCMS (ESI) m/z: [M + H]+ = 780.35 D123 LCMS (ESI) m/z: [M + H]+ = 780.25D124 LCMS (ESI) ¹H NMR (300 MHz, Methanol-d4) δ 7.65 (d, J = 8.3 Hz,1H), 7.57 (s, m/z: 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.73 (s, 2H), 6.66(dd, J = 8.4, 2.1 Hz, [M + H]+ = 849.30. 1H), 5.07 (dd, J = 12.2, 5.5Hz, 1H), 4.38 (d, J = 15.8 Hz, 4H), 4.02 (d, J = 9.2 Hz, 4H), 3.97 (s,6H), 3.79 (s, 3H), 3.67-3.63 (m, 4H), 3.55 (t, J = 5.5 Hz, 2H),2.92-2.69 (m, 7H), 2.67-2.54 (m, 6H), 2.16-2.08 (m, 1H), 1.89 (s, 4H),1.15 (s, 6H). D125 ¹H NMR (300 MHz, DMSO-d6, D20) δ 7.91-7.80 (m, 1H),7.59 (s, 1H), 7.36-7.25 (m, 2H), 6.70 (s, 2H), 5.11 (dd, J = 12.8, 5.4Hz, 1H), 4.75 (t, J = 6.8 Hz, 1H), 4.30-4.09 (m, 4H), 3.85 (s, 6H),3.61-3.60 (m, 5H), 3.47-3.35 (m, 5H), 3.19-2.77 (m, 8H), 2.66-2.57 (m,5H), 2.12-1.74 (m, 5H), 1.55-1.34 (m, 2H), 1.32-1.16 (m, 6H), 1.05 (t, J= 7.0 Hz, 1H). D126 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.14 (s,1H), 8.25 (s, 1H, FA), 7.91 m/z: (d, J = 8.1 Hz, 1H), 7.88-7.80 (m, 2H),7.61 (s, 1H), 6.57 (s, 3H), [M + H]+ = 818.45. 5.17 (dd, J = 12.9, 5.4Hz, 1H), 4.21 (s, 2H), 3.77 (s, 6H), 3.62 (s, 3H), 3.49 (s, 4H),3.42-3.39 (d, J = 5.5 Hz, 6H), 3.01 (s, 3H), 2.93-2.70 (m, 2H), 2.59 (d,J = 4.1 Hz, 5H), 2.14-2.00 (m, 1H), 1.64 (s, 4H), 1.41 (s, 6H). D127LCMS (ESI) ¹H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 2H), 7.72 (d, J =8.4 Hz, m/z: 1H), 7.58 (s, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.27 (dd, J =8.5, 2.4 Hz, [M + H]+ = 821.50. 1H), 6.73 (s, 2H), 5.61-5.54 (m, 1H),5.09 (dd, J = 12.5, 5.4 Hz, 1H), 4.36 (s, 4H), 3.95 (s, 6H), 3.64 (s,4H), 3.56-3.49 (m, 6H), 3.28- 3.22 (m, 2H), 3.18-3.13 (m, 2H), 2.91-2.83(m, 1H), 2.78 (s, 4H), 2.75-2.40 (m, 12H), 2.16-2.08 (m, 1H). D128 LCMS(ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.16 (s, 1H, FA), 7.83m/z: (d, J = 8.1 Hz, 1H), 7.63 (s, 1H), 7.31-7.25 (m, 2H), 6.63 (s, 2H),[M + H]+ = 878.44. 6.58 (q, J = 4.4 Hz, 1H), 5.12 (dd, J = 12.9, 5.4 Hz,1H), 4.98 (p, J = 6.7 Hz, 1H), 4.22 (s, 2H), 3.81 (s, 6H), 3.74 (s, 2H),3.50 (s, 3H), 3.41 (t, J = 5.6 Hz, 7H), 3.01 (d, J = 10.0 Hz, 2H),2.94-2.86 (m, 1H), 2.62- 2.57 (m, 4H), 2.46-2.38 (m, 3H), 2.31-2.13 (m,4H), 2.09-2.00 (m, 1H), 1.96-1.87 (m, 1H), 1.84-1.75 (m, 2H), 1.68-1.47(m, 5H), 1.41-1.29 (m, 1H), 1.25-1.08 (m, 2H), 0.84 (d, J = 6.4 Hz, 3H).D129 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.27 (s, 1H,FA), 7.69 m/z: (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.34 (d, J = 2.3 Hz,1H), 7.26 (dd, J = [M + H]+ = 821.35. 8.7, 2.2 Hz, 1H), 6.69-6.58 (m,3H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 4.22 (s, 2H), 3.96-3.87 (m, 2H),3.83 (s, 8H), 3.50 (s, 3H), 3.46- 3.39 (m, 8H), 3.14-2.98 (m, 2H),2.94-2.74 (m, 3H), 2.60 (d, J = 4.2 Hz, 3H), 2.57-2.54 (m, 2H),2.46-2.41 (m, 2H), 2.38-2.29 (m, 2H), 2.20 (s, 1H), 2.06-1.98 (m, 1H),1.85-1.78 (m, 1H), 1.76- 1.68 (m, 1H), 1.57-1.48 (m, 1H), 1.43-1.32 (m,1H). D130 LCMS (ESI) ¹H NMR (300 MHz, Methanol-d4) δ 7.63 (d, J = 8.5Hz, 1H), 7.43 (d, m/z: [M + H]+ = J = 2.6 Hz, 1H), 7.28 (dd, J = 5.9,2.1 Hz, 2H), 7.20 (d, J = 8.4 Hz, 1H), 823.25 6.56 (s, 2H), 5.09 (dd, J= 12.3, 5.4 Hz, 1H), 4.68-4.57 (m, 1H), 4.41- 4.14 (m, 2H), 3.88 (d, J =1.1 Hz, 6H), 3.72-3.60 (m, 3H), 3.59- 3.49 (m, 4H), 3.30-3.18 (m, 4H),3.06-2.86 (m, 4H), 2.90-2.76 (m, 5H), 2.78-2.36 (m, 10H), 2.30-2.11 (m,2H), 2.07-1.76 (m, 3H), 1.44-1.28 (m, 1H). D131 712.49 D132 767.52 D133746.3 D134 774.3 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.13 (s,1H), 7.95- 7.84 (m, 2H), 7.83 (s, 2H), 7.60 (s, 1H), 6.56 (s, 3H), 5.73(s, 2H), 5.13 (dd, J = 12.7, 5.4 Hz, 1H), 4.19 (s, 2H), 3.47 (s, 4H),3.38 (t, J = 5.6 Hz, 2H), 3.30 (d, J = 8.7 Hz, 1H), 3.28 (s, 4H), 2.87(td, J = 16.8, 15.2, 5.3 Hz, 1H), 2.57 (d, J = 4.2 Hz, 4H), 2.51 (s,1H), 2.18 (t, J = 10.0 Hz, 2H), 2.05 (dd, J = 10.4, 4.7 Hz, 1H),1.94-1.84 (m, 2H), 1.54 (d, J = 5.9 Hz, 4H). D135 762.4 1H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.12 (s, 1H), 7.95- 7.84 (m, 1H), 7.82 (dd, J= 7.4, 3.8 Hz, 2H), 7.60 (d, J = 7.0 Hz, 1H), 6.68 (s, 1H), 6.61 (d, J =1.8 Hz, 2H), 6.56 (d, J = 4.3 Hz, 1H), 5.73 (s, 1H), 5.13 (dd, J = 12.8,5.3 Hz, 1H), 4.19 (s, 2H), 3.86-3.78 (m, 7H), 3.48 (t, J = 3.1 Hz, 3H),3.39 (t, J = 5.6 Hz, 2H), 3.24 (dd, J = 16.5, 8.3 Hz, 1H), 2.93-2.80 (m,3H), 2.73 (s, 1H), 2.57 (dd, J = 4.2, 1.5 Hz, 4H), 2.38 (dt, J = 26.0,9.7 Hz, 2H), 2.19 (dt, J = 20.1, 9.5 Hz, 2H), 2.08-2.00 (m, 1H), 1.95(dd, J = 13.3, 7.0 Hz, 2H). D136 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ11.08 (s, 1H), 8.21 (s, 2H, FA), 7.64 m/z: (t, J = 4.1 Hz, 2H), 6.78 (d,J = 2.1 Hz, 1H), 6.68-6.57 (m, 4H), 5.05 [M + H]⁺ = 849.60. (dd, J =12.9, 5.4 Hz, 1H), 4.22 (s, 2H), 3.81 (s, 6H), 3.77-3.68 (m, 6H), 3.50(s, 3H), 3.41 (t, J = 5.6 Hz, 2H), 2.98 (s, 2H), 2.94-2.83 (m, 1H),2.63-2.52 (m, 7H), 2.47-2.19 (m, 6H), 2.10 (d, J = 7.0 Hz, 2H),2.04-1.95 (m, 1H), 1.80-1.72 (m, 4H), 1.68 (d, J = 12.7 Hz, 2H),1.61-1.50 (m, 1H), 1.23-1.10 (m, 2H). D137 LCMS (ESI) ¹H NMR (400 MHz,DMSO-d6) δ 11.15 (s, 1H), 8.21 (s, 1H FA), 7.91 m/z: (dd, J = 7.6, 0.9Hz, 1H), 7.88-7.81 (m, 2H), 7.63 (s, 1H), 6.66-6.51 [M + H]+ = 832.40.(m, 3H), 5.17 (dd, J = 12.8, 5.4 Hz, 1H), 4.21 (s, 2H), 3.77 (s, 6H),3.40 (t, J = 5.5 Hz, 4H), 2.94-2.85 (m, 1H), 2.77 (t, J = 6.8 Hz, 2H),2.63-2.54 (m, 7H), 2.42 (s, 4H), 2.12-2.00 (m, 1H), 1.62-1.44 (m, 6H),1.41 (s, 6H). D138 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H),8.25 (s, 1H, FA), 7.69 m/z: (d, J = 8.6 Hz, 1H), 7.64 (s, 1H), 7.35 (d,J = 2.3 Hz, 1H), 7.27 (dd, J = [M + H]+ = 835.41. 8.7, 2.3 Hz, 1H), 6.65(s, 2H), 6.61 (q, J = 4.4 Hz, 1H), 5.08 (dd, J = 12.9, 5.3 Hz, 1H), 4.22(s, 2H), 4.00-3.92 (m, 1H), 3.92-3.78 (m, 8H), 3.50 (s, 5H), 3.47-3.38(m, 9H), 3.13-3.05 (m, 1H), 2.94- 2.82 (m, 2H), 2.63-2.55 (m, 5H),2.44-2.24 (m, 4H), 2.07-1.99 (m, 1H), 1.95-1.72 (m, 3H), 1.66-1.49 (m,3H), 1.41-1.30 (m, 1H). D139 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ11.08 (s, 1H), 8.18 (s, 2H, FA), 7.71- m/z: 7.60 (m, 2H), 7.34 (d, J =2.1 Hz, 1H), 7.29-7.22 (m, 1H), 6.62- [M + H]+ = 824.50. 6.55 (m, 3H),5.07 (dd, J = 12.6, 5.3 Hz, 1H), 4.22 (s, 2H), 3.78 (s, 6H), 3.56-3.49(m, 6H), 3.45-3.38 (m, 8H), 2.93-2.82 (m, 1H), 2.66-2.53 (m, 8H),2.47-2.31 (m, 12H), 2.06-1.98 (m, 1H). D140 LCMS (ESI) ¹H NMR (300 MHz,DMSO-d6) δ 11.08 (s, 1H), 8.15 (s, 1H, FA), 7.72- m/z: 7.62 (m, 2H),7.34 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 6.67- [M + H]+ =908.55. 6.56 (m, 3H), 5.07 (dd, J = 12.7, 5.3 Hz, 1H), 4.22 (s, 2H),3.84- 3.73 (m, 8H), 3.60 (s, 2H), 3.50 (s, 3H), 3.46-3.38 (m, 9H), 2.95-2.83 (m, 1H), 2.76-2.65 (m, 3H), 2.64-2.53 (m, 9H), 2.40-2.23 (m, 6H),2.17 (s, 2H), 2.08-1.98 (m, 1H), 1.91-1.80 (m, 2H), 1.67- 1.51 (m, 4H).D141 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.18 (s, 2H),7.74- m/z: [M + H]+ = 7.47 (m, 2H), 7.26 (d, J = 2.2 Hz, 1H), 7.19 (dd,J = 8.7, 2.3 Hz, 1H), 851.51 6.54 (s, 3H), 5.03 (dd, J = 12.9, 5.4 Hz,1H), 4.19 (s, 2H), 3.99 (d, J = 13.0 Hz, 2H), 3.81 (s, 2H), 3.74 (s,6H), 3.46 (s, 3H), 3.37 (d, J = 5.7 Hz, 2H), 2.95-2.85 (m, 3H), 2.57 (d,J = 4.3 Hz, 3H), 2.14 (t, J = 7.5 Hz, 2H), 2.03-1.95 (m, 1H), 1.75-1.64(m, 4H), 1.07 (d, J = 5.7 Hz, 7H), 1.00 (d, J = 6.6 Hz, 2H). D142 LCMS(ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.14 (s, 1H), 7.91-m/z: [M + H]+ = 7.81 (m, 2H), 7.60 (s, 1H), 6.56 (d, J = 3.9 Hz, 3H),5.13 (dd, J = 12.7, 707.34 5.4 Hz, 1H), 4.19 (s, 2H), 3.77 (s, 5H), 3.55(s, 2H), 3.48 (d, J = 10.1 Hz, 5H), 3.37 (t, J = 5.7 Hz, 3H), 3.19-3.14(m, 2H), 2.87 (ddd, J = 16.7, 13.6, 5.4 Hz, 1H), 2.67-2.59 (m, 1H), 2.57(d, J = 4.2 Hz, 3H), 2.11-1.98 (m, 1H). D143 LCMS (ESI) m/z: [M + H]+ =735.38 D144 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.22(s, 1H, FA), 7.70- m/z: [M + H]+ = 7.59 (m, 2H), 6.91 (d, J = 2.1 Hz,1H), 6.81 (dd, J = 8.6, 2.2 Hz, 1H), 821.5 6.63-6.53 (m, 3H), 5.06 (dd,J = 12.6, 5.4 Hz, 1H), 4.21 (s, 2H), 4.00 (q, J = 8.5 Hz, 2H), 3.88-3.81(m, 2H), 3.78 (s, 6H), 3.68-3.57 (m, 3H), 3.54-3.45 (m, 8H), 3.25-3.16(m, 4H), 3.10 (q, J = 7.3 Hz, 2H), 2.95-2.81 (m, 1H), 2.62-2.55 (m, 6H),2.26-2.17 (m, 2H), 2.07- 1.96 (m, 1H). D145 LCMS (ESI) ¹H NMR (300 MHz,Methanol-d4) δ 7.82-7.76 (m, 1H), 7.58 (s, 1H), m/z: 7.51 (d, J = 2.3Hz, 1H), 7.38 (dd, J = 8.5, 2.2 Hz, 1H), 6.73 (s, 2H), [M + H]+ =851.65. 5.11 (dd, J = 12.4, 5.4 Hz, 1H), 4.37 (d, J = 4.6 Hz, 4H), 4.25(d, J = 13.6 Hz, 2H), 3.96 (d, J = 3.5 Hz, 6H), 3.75-3.60 (m, 6H), 3.60-3.52 (m, 3H), 3.51-3.41 (m, 2H), 3.24-3.07 (m, 4H), 2.92-2.70 (m, 6H),2.63 (s, 2H), 2.18-1.85 (m, 4H), 1.84-1.58 (m, 4H), 1.57- 1.48 (m, 6H).D146 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.17 (s, 1H,FA), 7.68 m/z: (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.34 (d, J = 2.2 Hz,1H), 7.25 (dd, J = [M + H]+ = 807.55. 8.7, 2.3 Hz, 1H), 6.66-6.56 (m,3H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.22 (s, 2H), 3.84 (s, 2H), 3.82(s, 6H), 3.59 (s, 2H), 3.50 (s, 4H), 3.48 (s, 2H), 3.43-3.39 (m, 8H),2.93-2.84 (m, 1H), 2.62-2.58 (m, 4H), 2.58-2.55 (m, 1H), 2.35 (t, J =4.9 Hz, 4H), 2.27-2.19 (m, 2H), 2.06- 1.99 (m, 1H), 1.95 (t, J = 10.1Hz, 2H). D147 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.15(s, 1H, FA), 7.68 m/z: (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.34 (s, 1H),7.25 (dd, J = 8.9, 2.3 [M + H]+ = 827.35. Hz, 1H), 6.59 (s, 3H), 5.07(dd, J = 12.8, 5.4 Hz, 1H), 4.22 (s, 2H), 3.79 (s, 6H), 3.57 (s, 2H),3.50 (s, 3H), 3.46-3.37 (m, 10H), 2.94- 2.82 (m, 1H), 2.65-2.55 (m,11H), 2.38-2.30 (m, 2H), 2.06-1.98 (m, 1H), 1.81 (t, J = 12.2 Hz, 2H),1.74-1.54 (m, 2H). D148 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s,1H), 8.18 (s, 1H, FA), 7.68 m/z: (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.34(d, J = 2.2 Hz, 1H), 7.26 (dd, J = [M + H]+ = 809.35. 8.8, 2.3 Hz, 1H),6.64 (s, 2H), 6.59 (q, J = 4.4 Hz, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H),4.21 (s, 2H), 3.90 (s, 2H), 3.82 (s, 6H), 3.50 (s, 3H), 3.44-3.39 (m,8H), 3.37-3.28 (m, 5H), 3.08 (t, J = 8.9 Hz, 2H), 2.94- 2.80 (m, 3H),2.62-2.56 (m, 4H), 2.30 (t, J = 7.2 Hz, 2H), 2.21- 2.13 (m, 1H),2.06-1.94 (m, 2H), 1.61-1.49 (m, 2H), 1.48-1.39 (m, 1H). D149 LCMS (ESI)¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.23 (s, 2H, FA), 7.83 m/z:[M + H]+ = (dd, J = 8.2, 2.8 Hz, 1H), 7.63 (s, 1H), 7.34-7.23 (m, 2H),6.66-6.57 824.75 (m, 3H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.98-4.90 (m,1H), 4.69 (p, J = 7.1 Hz, 1H), 4.22 (s, 2H), 3.80 (d, J = 4.7 Hz, 6H),3.71 (s, 2H), 3.50 (s, 3H), 3.40 (t, J = 5.5 Hz, 2H), 3.01-2.92 (m, 2H),2.92-2.84 (m, 1H), 2.74-2.68 (m, 1H), 2.65-2.57 (m, 4H), 2.56-2.52 (m,2H), 2.42-2.25 (m, 3H), 2.22-2.14 (m, 1H), 2.10-1.98 (m, 6H), 1.93- 1.57(m, 4H), 1.49 (s, 1H), 1.25-1.07 (m, 2H). D150 LCMS (ESI) ¹H NMR (400MHz, DMSO-d6) δ 11.09 (s, 1H), 8.21 (s, 2H, FA), 7.68 m/z: [M + H]+ =(d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.26 (dd, J= 769.45 8.7, 2.3 Hz, 1H), 6.66 (t, J = 5.5 Hz, 1H), 6.60 (s, 2H), 5.08(dd, J = 12.9, 5.4 Hz, 1H), 4.23 (s, 2H), 3.79 (s, 6H), 3.54 (s, 2H),3.50 (s, 3H), 3.46-3.39 (m, 7H), 3.22 (q, J = 6.5 Hz, 3H), 2.93-2.83 (m,1H), 2.64-2.53 (m, 6H), 2.43 (t, J = 7.1 Hz, 2H), 2.21 (s, 6H),2.06-1.98 (m, 1H). D151 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.08 (s,1H), 8.15 (s, 2H), 7.68 (d, m/z: [M + H]+ = J = 8.5 Hz, 1H), 7.63 (s,1H), 7.34 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.6, 839.55 2.2 Hz, 1H),6.59 (s, 3H), 5.08 (dd, J = 12.7, 5.3 Hz, 1H), 4.21 (s, 2H), 3.79 (s,6H), 3.76-3.67 (m, 1H), 3.52 (s, 2H), 3.49 (s, 5H), 3.48- 3.35 (m, 10H),2.98-2.80 (m, 1H), 2.75-2.55 (m, 7H), 2.50-2.43 (m, 2H), 2.36-2.26 (m,2H), 2.19-1.97 (m, 2H), 1.85 (t, J = 10.7 Hz, 1H), 1.61-1.32 (m, 4H).D152 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.14 (s, 1H,FA), 7.68 m/z: (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.35 (s, 1H), 7.26(dd, J = 8.7, 2.3 [M + H]+ = 825.70. Hz, 1H), 6.62 (s, 2H), 6.61-6.57(m, 1H), 5.08 (dd, J = 12.9, 5.3 Hz, 1H), 4.21 (s, 2H), 3.81 (s, 6H),3.78-3.73 (m, 1H), 3.65 (s, 2H), 3.50 (s, 4H), 3.47-3.42 (m, 6H),3.42-3.37 (m, 5H), 2.95-2.82 (m, 2H), 2.74-2.69 (m, 1H), 2.60 (d, J =4.3 Hz, 5H), 2.58-2.54 (m, 4H), 2.31-2.21 (m, 1H), 2.12-1.97 (m, 2H),1.68-1.51 (m, 2H). D153 LCMS (ESI) ¹H NMR (400 MHz, Methanol-d4) δ 8.49(s, 2H, FA), 7.74 (dd, J = m/z: 16.5, 8.4 Hz, 1H), 7.57 (s, 1H), 7.27(s, 1H), 7.13 (d, J = 8.8 Hz, 1H), [M + H]+ = 835.60. 6.70 (s, 2H), 5.11(dd, J = 12.7, 5.4 Hz, 1H), 4.34 (d, J = 11.5 Hz, 4H), 4.05-3.88 (m,8H), 3.78 (d, J = 12.0 Hz, 2H), 3.71-3.61 (m, 5H), 3.57-3.40 (m, 5H),3.12-2.99 (m, 2H), 2.89-2.68 (m, 9H), 2.62 (s, 3H), 2.18-2.09 (m, 1H),1.93 (d, J = 13.8 Hz, 2H), 1.84-1.78 (m, 1H), 1.73-1.63 (m, 1H), 1.52(s, 3H), 1.39-1.27 (m, 1H). D154 LCMS (ESI) ¹H NMR (300 MHz,Methanol-d4) δ 8.51 (s, 2H), 7.70 (d, J = 8.5 Hz, m/z: 1H), 7.57 (s,1H), 7.37 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.6, 2.3 Hz, [M + H]+ =859.75. 1H), 6.72 (s, 2H), 5.09 (dd, J = 12.3, 5.4 Hz, 1H), 4.37 (d, J =9.4 Hz, 4H), 3.95 (s, 6H), 3.70-3.62 (m, 4H), 3.60-3.45 (m, 7H), 3.18(t, J = 12.6 Hz, 2H), 2.95-2.69 (m, 12H), 2.68-2.59 (m, 2H), 2.58-2.46(m, 1H), 2.19-2.07 (m, 3H), 2.03-1.86 (m, 2H). D155 LCMS (ESI) ¹H NMR(300 MHz, Methanol-d4) δ 7.79 (d, J = 8.4 Hz, 1H), 7.59 (s, m/z: 1H),7.50 (d, J = 2.1 Hz, 1H), 7.41-7.34 (m, 1H), 6.75 (s, 2H), 5.12 [M + H]+= 859.50. (dd, J = 12.4, 5.4 Hz, 1H), 4.50 (s, 2H), 4.36 (s, 2H), 3.96(s, 6H), 3.94- 3.74 (m, 3H), 3.70-3.62 (m, 5H), 3.61-3.39 (m, 8H),3.39-3.35 (m, 2H), 3.23-3.19 (m, 1H), 2.87-2.71 (m, 6H), 2.68-2.61 (m,2H), 2.40-2.21 (m, 3H), 2.18-2.09 (m, 1H), 1.96-1.80 (m, 2H). D156737.88 D157 723.39 D158 738.37 D159 751.46 D161 751.39 NA D162 751.32 NAD163 765.39 NA D164 766.4 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H),8.13 (s, 1H), 7.65- 7.57 (m, 2H), 6.75 (d, J = 2.1 Hz, 1H), 6.61 (dd, J= 8.4, 2.1 Hz, 1H), 6.56 (s, 2H), 6.54 (d, J = 4.5 Hz, 1H), 5.03 (dd, J= 12.9, 5.4 Hz, 1H), 4.19 (s, 2H), 4.05 (t, J = 7.7 Hz, 2H), 3.80 (dd, J= 8.9, 4.9 Hz, 2H), 3.76 (s, 5H), 3.54 (s, 2H), 3.47 (s, 3H), 3.37 (s,1H), 3.25 (q, J = 5.9 Hz, 1H), 3.15 (s, 1H), 2.86 (ddd, J = 17.6, 13.9,5.4 Hz, 1H), 2.61- 2.50 (m, 4H), 2.47-2.42 (m, 4H), 2.34-2.29 (m, 4H),1.99 (dp, J = 12.2, 4.6, 4.0 Hz, 1H). D165 737.4 1H NMR (400 MHz,DMSO-d6) δ 11.03 (s, 1H), 8.15 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 6.76(d, J = 2.1 Hz, 1H), 6.62 (dd, J = 8.4, 2.1 Hz, 1H), 6.57 (s, 2H), 6.54(dd, J = 5.8, 3.3 Hz, 1H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.19 (s,2H), 3.90 (q, J = 8.4 Hz, 4H), 3.77 (s, 6H), 3.47 (s, 3H), 3.38 (t, J =5.5 Hz, 2H), 3.15 (s, 1H), 3.10 (s, 0H), 2.86 (ddd, J = 17.4, 13.9, 5.5Hz, 1H), 2.77 (s, 2H), 2.61-2.48 (m, 6H), 2.05-1.93 (m, 3H). D166 737.41H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.13 (s, 1H), 7.65- 7.58 (m,2H), 6.80 (d, J = 2.0 Hz, 1H), 6.72 (dd, J = 8.3, 2.0 Hz, 1H), 6.56 (d,J = 12.0 Hz, 3H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.28 (dt, J = 8.3,4.2 Hz, 1H), 4.19 (s, 2H), 3.77 (s, 6H), 3.78-3.66 (m, 2H), 3.47 (s,3H), 3.38 (t, J = 5.6 Hz, 2H), 3.15 (s, 1H), 2.96-2.79 (m, 2H), 2.72 (s,1H), 2.57 (d, J = 4.3 Hz, 4H), 2.51 (s, 1H), 2.45 (s, 0H), 2.03-1.85 (m,2H). D167 LCMS ¹H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.24 (s, 2H,FA), 7.69- (ESI) m/z: 7.59 (m, 2H), 6.89 (d, J = 2.1 Hz, 1H), 6.80 (dd,J = 8.6, 2.2 Hz, 1H), [M + H]+ = 807. 6.60 (s, 3H), 5.05 (dd, J = 12.5,5.4 Hz, 1H), 4.21 (s, 2H), 3.79 (s, 6H), 3.70-3.63 (m, 4H), 3.54-3.47(m, 7H), 3.43-3.37 (m, 6H), 3.18- 3.10 (m, 4H), 3.04 (s, 2H), 2.91-2.82(m, 1H), 2.63-2.56 (m, 5H), 2.39-2.31 (m, 1H), 2.15 (t, J = 6.8 Hz, 2H),2.06-1.95 (m, 1H). D168 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.09 (s,1H), 7.69 (d, J = 8.5 Hz, m/z: 1H), 7.64 (s, 1H), 7.35 (d, J = 2.3 Hz,1H), 7.26 (dd, J = 8.7, 2.3 Hz, [M + H]+ = 981.35. 1H), 6.69 (s, 2H),6.60 (q, J = 4.4 Hz, 1H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 4.22 (s, 2H),4.14 (s, 2H), 4.00-3.91 (m, 2H), 3.86 (s, 6H), 3.70- 3.56 (m, 2H), 3.50(s, 3H), 3.45-3.39 (m, 6H), 2.94-2.83 (m, 2H), 2.63-2.56 (m, 6H),2.50-2.42 (m, 7H), 2.06-1.97 (m, 1H). D169 LCMS (ESI) ¹H NMR (400 MHz,DMSO-d6) δ 11.08 (s, 1H), 8.21 (s, 1H, FA), 7.68 m/z: (d, J = 8.5 Hz,1H), 7.63 (s, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.26 (dd, J = [M + H]+ =795.35. 8.7, 2.3 Hz, 1H), 6.64-6.54 (m, 3H), 5.07 (dd, J = 12.9, 5.4 Hz,1H), 4.22 (s, 2H), 3.80 (s, 6H), 3.73 (s, 2H), 3.50 (s, 4H), 3.45-3.37(m, 8H), 2.95-2.79 (m, 2H), 2.66-2.56 (m, 6H), 2.49-2.44 (m, 3H),2.40-2.32 (m, 3H), 2.31-2.26 (m, 2H), 2.07-1.96 (m, 1H), 1.91- 1.81 (m,1H), 1.46-1.34 (m, 1H). D170 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ11.08 (s, 1H), 8.19 (s, 1H, FA), 7.68- m/z: 7.61 (m, 2H), 7.32 (d, J =2.3 Hz, 1H), 7.24 (dd, J = 8.7, 2.3 Hz, 1H), [M + H]+ = 795.35. 6.58 (s,3H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.21 (s, 2H), 4.04 (d, J = 12.7Hz, 2H), 3.77 (s, 6H), 3.51 (d, J = 11.7 Hz, 6H), 3.40 (t, J = 5.6 Hz,4H), 2.98-2.86 (m, 3H), 2.63-2.55 (m, 5H), 2.48-2.37 (m, 8H), 2.06-1.97(m, 1H), 1.83 (d, J = 12.1 Hz, 2H), 1.43 (q, J = 11.7, 11.0 Hz, 2H).D171 LCMS (ESI) ¹H NMR (300 MHz, Methanol-d4) δ 7.73 (d, J = 8.2 Hz,1H), 7.57 (s, m/z: 1H), 6.96 (d, J = 2.1 Hz, 1H), 6.81 (dd, J = 8.2, 2.1Hz, 1H), 6.73 (d, [M + H]+ = 823.55 J = 4.1 Hz, 2H), 5.09 (dd, J = 12.3,5.4 Hz, 1H), 4.50-4.20 (m, 9H), 3.96 (d, J = 4.8 Hz, 6H), 3.64 (s, 3H),3.62-3.52 (m, 4H), 3.25-3.02 (m, 4H), 2.96-2.82 (m, 4H), 2.81-2.69 (m,5H), 2.67-2.60 (m, 2H), 2.18-1.86 (m, 4H), 1.80-1.52 (m, 4H). D172 LCMS(ESI) ¹H NMR (300 MHz, Methanol-d4) δ 8.45 (s, 2H, FA), 7.68 (d, J = 8.4m/z: [M + H]+ = Hz, 1H), 7.58 (s, 1H), 7.09 (d, J = 2.1 Hz, 1H), 6.94(dd, J = 8.5, 2.2 835.80. Hz, 1H), 6.71 (s, 2H), 5.08 (dd, J = 12.4, 5.4Hz, 1H), 4.74 (s, 1H), 4.35 (s, 4H), 4.14 (s, 1H), 3.93 (s, 6H),3.71-3.60 (m, 5H), 3.58- 3.44 (m, 4H), 3.24 (d, J = 10.4 Hz, 1H),3.16-3.01 (m, 3H), 2.97- 2.70 (m, 8H), 2.63 (t, J = 5.7 Hz, 2H),2.28-2.07 (m, 3H), 1.96 (d, J = 13.4 Hz, 2H), 1.75-1.49 (m, 5H). D173LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.20 (s, 2H, FA),7.69- m/z: 7.61 (m, 2H), 7.27 (d, J = 2.2 Hz, 1H), 7.21 (dd, J = 8.8,2.4 Hz, 1H), [M + H]+ = 851.40. 6.69-6.54 (m, 3H), 5.07 (dd, J = 12.9,5.4 Hz, 1H), 4.22 (s, 2H), 4.03- 3.93 (m, 3H), 3.79 (s, 7H), 3.63 (s,3H), 3.50 (s, 3H), 3.40 (t, J = 5.5 Hz, 2H), 2.99-2.84 (m, 5H), 2.59 (d,J = 4.3 Hz, 3H), 2.58-2.53 (m, 4H), 2.25 (s, 3H), 2.23-2.15 (m, 2H),2.06-1.97 (m, 1H), 1.88- 1.71 (m, 2H), 1.63 (d, J = 12.5 Hz, 2H),1.56-1.43 (m, 2H), 1.31 (s, 3H), 1.21-1.07 (m, 2H). D174 LCMS (ESI) ¹HNMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.18 (s, 1H, FA), 7.68 m/z: (d,J = 8.5 Hz, 1H), 7.62 (s, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.25 (dd, J =[M + H]+ = 849.35. 8.7, 2.0 Hz, 1H), 6.59 (s, 3H), 5.07 (dd, J = 12.8,5.4 Hz, 1H), 4.21 (s, 2H), 3.78 (s, 6H), 3.60-3.37 (m, 15H), 2.96-2.80(m, 4H), 2.63- 2.53 (m, 6H), 2.20 (s, 2H), 2.13-1.95 (m, 3H), 1.60-1.50(m, 2H), 1.45-1.31 (m, 2H), 1.28-1.13 (m, 1H), 0.39 (s, 2H), 0.17 (s,2H). D175 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.19 (s,1H, FA), 7.70- m/z: 7.66 (m, 1H), 7.63 (d, J = 2.7 Hz, 1H), 7.35 (s,1H), 7.26 (t, J = 7.9 [M + H]+ = 922.35. Hz, 1H), 6.62-6.56 (m, 3H),5.07 (dd, J = 13.0, 5.4 Hz, 1H), 4.21 (s, 2H), 3.77 (d, J = 2.7 Hz, 6H),3.61 (s, 2H), 3.57-3.52 (m, 4H), 3.50- 3.47 (m, 4H), 3.44-3.40 (m, 7H),3.34-3.30 (m, 3H), 2.94-2.84 (m, 1H), 2.63-2.58 (m, 6H), 2.57-2.54 (m,5H), 2.48-2.41 (m, 3H), 2.41-2.23 (m, 2H), 2.06-1.97 (m, 1H), 1.72-1.58(m, 2H), 1.56- 1.41 (m, 2H). D176 792.29 ¹H NMR (400 MHz, DMSO-d6) δ11.10 (d, J = 15.8 Hz, 1H), 8.14 (s, 2H), 7.78 (d, J = 16.8 Hz, 2H),7.60 (s, 1H), 6.57 (d, J = 15.8 Hz, 3H), 5.20-4.89 (m, 2H), 4.19 (s,2H), 3.96 (s, 3H), 3.79 (d, J = 3.5 Hz, 7H), 3.48 (s, 3H), 2.57 (d, J =4.2 Hz, 3H), 1.88-1.64 (m, 1H), 1.45- 1.24 (m, 2H). D177 764.92 D178794.46 D179 LCMS (ESI) m/z: [M + H]+ = 780.46 D180 LCMS (ESI) m/z: [M +H]+ = 766.39 D181 LCMS (ESI) m/z: [M + H]+ = 820.5 D182 LCMS (ESI) m/z:[M + H]+ = 792.91 D183 LCMS (ESI) m/z: [M + H]+ = 767.92 D184 LCMS (ESI)¹H NMR (300 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.20 (s, 2H, FA), 7.79- m/z:[M + H]+ = 7.50 (m, 2H), 6.76 (d, J = 2.0 Hz, 1H), 6.67 (d, J = 7.8 Hz,1H), 6.62 781.45 (s, 2H), 5.05 (dd, J = 12.6, 5.4 Hz, 1H), 4.88 (t, J =5.4 Hz, 1H), 4.24 (s, 2H), 4.21-4.10 (m, 1H), 4.00 (d, J = 9.7 Hz, 1H),3.80 (s, 6H), 3.75-3.59 (m, 4H), 3.51 (s, 4H), 3.46-3.37 (m, 3H), 3.20(d, J = 6.2 Hz, 2H), 3.08 (t, J = 8.0 Hz, 1H), 2.98-2.80 (m, 1H),2.71-2.59 (m, 3H), 2.58-2.54 (m, 2H), 2.29 (s, 6H), 2.08-1.91 (m, 2H),1.76 (d, J = 12.4 Hz, 1H). D185 LCMS (ESI) m/z: [M + H]+ = 795.25 D186LCMS (ESI) m/z: [M + H]+ = 867.6 D187 LCMS (ESI) ¹H NMR (300 MHz,DMSO-d6) δ 11.06 (s, 1H), 8.22 (s, 3H, FA), 7.66- m/z: [M + H]+ = 7.58(m, 2H), 6.83 (d, J = 2.0 Hz, 1H), 6.74 (dd, J = 8.3, 2.1 Hz, 1H),795.55 6.64-6.56 (m, 3H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.40-4.31 (m,1H), 4.22 (s, 2H), 3.80 (s, 8H), 3.62 (s, 2H), 3.50 (s, 3H), 3.41 (t, J= 5.5 Hz, 2H), 3.20 (d, J = 6.7 Hz, 2H), 2.96-2.77 (m, 3H), 2.63-2.53(m, 6H), 2.44 (t, J = 6.5 Hz, 3H), 2.31-2.25 (m, 6H), 2.07-1.90 (m, 3H).D188 LCMS (ESI) m/z: [M + H]+ = 809.65 D189 LCMS (ESI) ¹H NMR (300 MHz,DMSO-d6) δ 11.06 (s, 1H), 8.23 (s, 3H, FA), 7.76- m/z: [M + H]+ = 7.55(m, 2H), 6.79 (d, J = 2.1 Hz, 1H), 6.71-6.60 (m, 2H), 6.60 (s, 795.62H), 5.06 (dd, J = 12.7, 5.3 Hz, 1H), 4.23 (s, 2H), 4.06-3.87 (m, 4H),3.79 (s, 6H), 3.51 (s, 5H), 3.47-3.37 (m, 2H), 3.24-3.13 (m, 2H),2.98-2.75 (m, 4H), 2.68-2.51 (m, 7H), 2.19 (s, 6H), 2.04 (q, J = 12.6,9.6 Hz, 3H). D190 LCMS (ESI) m/z: [M + H]+ = 809.65 D191 LCMS (ESI) m/z:[M + H]+ = 809.45 D192 LCMS (ESI) m/z: [M + H]+ = 781.7 D193 LCMS (ESI)m/z: [M + H]+ = 936.55 D194 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.10(s, 1H), 8.19 (s, 2H, FA), 7.83 m/z: [M + H]+ = (d, J = 8.3 Hz, 1H),7.64 (s, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 824.35 8.3, 2.3Hz, 1H), 6.68 (t, J = 5.7 Hz, 1H), 6.61 (s, 2H), 5.12 (dd, J = 12.9, 5.4Hz, 1H), 4.25-4.13 (m, 4H), 3.80 (s, 6H), 3.63 (s, 3H), 3.50 (s, 4H),3.40 (t, J = 5.5 Hz, 2H), 3.30 (s, 2H), 3.24 (s, 2H), 3.03 (t, J = 6.2Hz, 2H), 2.96-2.81 (m, 1H), 2.66-2.55 (m, 4H), 2.28 (s, 7H), 2.15-2.03(m, 3H), 1.86-1.71 (m, 4H) D195 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ11.07 (s, 1H), 8.15 (s, 1H), 7.67 (d, m/z: J = 8.5 Hz, 1H), 7.63 (s,1H), 7.32 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.6, [M + H]+ = 837.65. 2.3Hz, 1H), 6.69 (s, 2H), 6.59 (q, J = 4.4 Hz, 1H), 5.06 (dd, J = 12.8, 5.4Hz, 1H), 4.22 (s, 2H), 4.16-4.00 (m, 4H), 3.85 (s, 6H), 3.54- 3.48 (m,7H), 3.03-2.89 (m, 4H), 2.86-2.67 (m, 4H), 2.63-2.57 (m, 4H), 2.31-2.25(m, 2H), 2.21 (s, 3H), 2.10-1.95 (m, 2H), 1.85- 1.71 (m, 4H), 1.69-1.59(m, 1H), 1.54-1.40 (m, 2H), 1.37-1.23 (m, 2H). D196 LCMS (ESI) ¹H NMR(300 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.18 (s, 2H, FA), 7.69- m/z: 7.61(m, 2H), 6.95 (d, J = 2.1 Hz, 1H), 6.86 (dd, J = 8.6, 2.2 Hz, 1H), [M +H]+ = 849.60. 6.64-6.55 (m, 3H), 5.06 (dd, J = 12.6, 5.4 Hz, 1H), 4.21(s, 2H), 3.79 (s, 6H), 3.70-3.61 (m, 4H), 3.50 (s, 3H), 3.40 (t, J = 5.6Hz, 2H), 3.30 (dd, J = 11.0, 2.6 Hz, 2H), 3.00-2.91 (m, 4H), 2.91-2.76(m, 2H), 2.65-2.52 (m, 10H), 2.44-2.38 (m, 2H), 2.32-2.23 (m, 2H), 2.04-1.94 (m, 1H), 1.63 (d, J = 12.2 Hz, 2H), 1.38-1.12 (m, 5H). D197 LCMS(ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.19 (s, 2H, FA), 7.68-m/z: 7.61 (m, 2H), 6.95 (d, J = 2.1 Hz, 1H), 6.87-6.81 (m, 1H), 6.59 (s,[M + H]+ = 837.42. 3H), 5.06 (dd, J = 12.4, 5.4 Hz, 1H), 4.22 (s, 2H),3.78 (s, 6H), 3.66- 3.53 (m, 5H), 3.50 (s, 4H), 3.41 (s, 2H), 3.21-3.10(m, 4H), 2.90- 2.80 (m, 3H), 2.60 (d, J = 4.2 Hz, 3H), 2.43-2.39 (m,2H), 2.18 (s, 3H), 2.13-1.98 (m, 4H), 1.90-1.79 (m, 1H), 1.62 (d, J =11.9 Hz, 2H), 1.38-1.04 (m, 6H). D198 LCMS (ESI) ¹H NMR (400 MHz,DMSO-d6) δ 11.07 (s, 1H), 8.20 (s, 2H, FA), 7.66- m/z: 7.61 (m, 2H),7.11 (d, J = 2.3 Hz, 1H), 7.03 (dd, J = 8.8, 2.4 Hz, 1H), [M + H]+ =837.65. 6.63-6.57 (m, 3H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.22 (s,2H), 3.79 (s, 6H), 3.69-3.59 (m, 7H), 3.50 (s, 3H), 3.40 (t, J = 5.5 Hz,2H), 2.99- 2.80 (m, 4H), 2.73 (t, J = 5.1 Hz, 2H), 2.62-2.54 (m, 6H),2.44 (t, J = 7.2 Hz, 2H), 2.19 (t, J = 11.0 Hz, 2H), 2.06-1.95 (m, 1H),1.85 (p, J = 6.2, 5.6 Hz, 2H), 1.59 (d, J = 11.9 Hz, 2H), 1.38-1.01 (m,6H). D199 LCMS (ESI) ¹H NMR (300 MHz, Methanol-d4) δ 8.54 (s, 1H), 7.66(d, J = 8.3 Hz, m/z: [M + H]+ = 1H), 7.58 (s, 1H), 6.84 (d, J = 2.1 Hz,1H), 6.74-6.66 (m, 3H), 5.07 835.60 (dd, J = 12.3, 5.4 Hz, 1H), 4.36 (s,2H), 4.33 (s, 2H), 4.17 (s, 4H), 3.95 (s, 6H), 3.71-3.62 (m, 4H),3.60-3.52 (m, 6H), 3.51-3.42 (m, 2H), 3.12-2.99 (m, 2H), 2.88-2.71 (m,6H), 2.68-2.59 (m, 4H), 2.17- 2.07 (m, 1H), 1.95 (d, J = 13.5 Hz, 2H),1.73-1.53 (m, 2H), 1.46- 1.36 (m, 2H). D200 LCMS (ESI) ¹H NMR (300 MHz,DMSO-d6) δ 11.06 (s, 1H), 8.16 (s, 1H, FA), 7.69- m/z: 7.60 (m, 2H),7.32 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.7, 2.3 Hz, 1H), [M + H]+ =851.95. 6.64-6.54 (m, 3H), 5.07 (dd, J = 12.7, 5.4 Hz, 1H), 4.22 (s,2H), 4.10 (d, J = 13.0 Hz, 2H), 3.80 (s, 6H), 3.69 (s, 2H), 3.50 (s,3H), 3.44- 3.37 (m, 5H), 3.00-2.87 (m, 5H), 2.84-2.66 (m, 2H), 2.63-2.56(m, 4H), 2.47-2.44 (m, 1H), 2.30-2.17 (m, 5H), 2.06-1.98 (m, 1H), 1.79(d, J = 12.3 Hz, 2H), 1.65 (d, J = 12.3 Hz, 2H), 1.55-1.41 (m, 2H),1.39-1.16 (m, 5H). D201 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.07 (s,1H), 8.19 (s, 1H, FA), 7.67 m/z: [M + H]+ = (d, J = 8.5 Hz, 1H), 7.63(s, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.24 (dd, J = 795.75 8.7, 2.3 Hz,1H), 6.62-6.54 (m, 3H), 5.07 (dd, J = 12.7, 5.3 Hz, 1H), 4.22 (s, 2H),3.79 (s, 6H), 3.53-3.49 (m, 6H), 3.43-3.39 (m, 8H), 2.93-2.82 (m, 3H),2.60 (d, J = 4.3 Hz, 8H), 2.25-2.16 (m, 1H), 2.10-1.98 (m, 3H), 1.71 (d,J = 11.9 Hz, 2H), 1.47-1.31 (m, 2H). D202 LCMS (ESI) ¹H NMR (300 MHz,DMSO-d6) δ 11.08 (s, 1H), 8.14 (s, 1H, FA), 7.70 m/z: (d, J = 8.5 Hz,1H), 7.64 (s, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.27 (dd, J = [M + H]+ =894.55. 8.8, 2.2 Hz, 1H), 6.72 (s, 2H), 6.60 (q, J = 4.2 Hz, 1H), 5.08(dd, J = 12.7, 5.4 Hz, 1H), 4.28-4.11 (m, 4H), 3.87 (s, 6H), 3.64 (s,2H), 3.51 (s, 3H), 3.49-3.40 (m, 9H), 3.15-3.00 (m, 4H), 2.97-2.82 (m,2H), 2.65-2.54 (m, 10H), 2.47-2.28 (m, 6H), 2.12-1.96 (m, 3H), 1.85-1.54 (m, 2H). D203 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H),8.17 (s, 1H FA), 7.84 m/z: (dd, J = 8.4, 4.2 Hz, 1H), 7.63 (d, J = 3.5Hz, 1H), 7.43 (s, 1H), 7.36 [M + H]+ = 868.50. (d, J = 8.4 Hz, 1H),6.65-6.53 (m, 3H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.25-4.15 (m, 4H),3.79 (d, J = 3.3 Hz, 6H), 3.69-3.54 (m, 5H), 3.50 (s, 3H), 3.45-3.29 (m,8H), 2.97-2.83 (m, 1H), 2.65-2.54 (m, 7H), 2.47-2.32 (m, 3H), 2.07-1.93(m, 3H), 1.75-1.60 (m, 2H), 1.59-1.44 (m, 2H). D204 853.65 D205 LCMS(ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.19 (s, 2H, FA), 7.68-m/z: [M + H]+ = 7.62 (m, 2H), 7.31 (d, J = 2.2 Hz, 1H), 7.23 (dd, J =8.7, 2.3 Hz, 1H), 837.75 6.66 (t, J = 5.1 Hz, 1H), 6.60 (s, 2H), 5.07(dd, J = 12.7, 5.4 Hz, 1H), 4.22 (s, 2H), 4.12-4.01 (m, 2H), 3.79 (s,6H), 3.59 (s, 2H), 3.50 (s, 3H), 3.41 (t, J = 5.4 Hz, 4H), 3.22-3.13 (m,4H), 2.95-2.81 (m, 4H), 2.65-2.55 (m, 3H), 2.25 (s, 8H), 2.05-1.96 (m,1H), 1.89-1.67 (m, 4H), 1.53-1.36 (m, 2H), 1.27-1.12 (m, 2H). D206 LCMS(ESI) m/z: [M + H]+ = 867.65 D207 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ11.06 (s, 1H), 8.24 (s, 2H, FA), 7.64 m/z: [M + H]+ = (d, J = 5.9 Hz,2H), 6.96-6.41 (m, 5H), 5.20-4.86 (m, 1H), 4.46- 809.7 4.12 (m, 2H),3.96 (t, J = 6.6 Hz, 6H), 3.79 (s, 6H), 3.65-3.30 (m, 9H), 3.11 (d, J =6.9 Hz, 2H), 2.77 (s, 4H), 2.23 (s, 6H), 2.15-1.92 (m, 3H), 1.75-1.55(m, 2H), 1.25-0.97 (m, 3H). D208 LCMS (ESI) m/z: [M + H]+ = 823.6 D209LCMS (ESI) m/z: [M + H]+ = 823.45 D210 LCMS (ESI) m/z: [M + H]+ = 809.45D211 LCMS (ESI) m/z: [M + H]+ = 795.55 D212 LCMS (ESI) m/z: [M + H]+ =809.35 D213 LCMS (ESI) m/z: [M + H]+ = 840.4 D214 LCMS (ESI) m/z: [M +H]+ = 920.4 D215 LCMS (ESI) m/z: [M + H]+ = 824.4 D216 LCMS (ESI) m/z:[M + H]+ = 920.4 D217 LCMS (ESI) m/z: [M + H]+ = 950.5 D218 LCMS (ESI)m/z: [M + H]+ = 934.55 D219 LCMS (ESI) m/z: [M + H]+ = 906.5 D220 LCMS(ESI) ¹H NMR (300 MHz, Methanol-d4) δ 8.47 (s, 2H, FA), 7.71-7.57 (m,m/z: [M + H]+ = 2H), 7.36 (s, 1H), 7.24 (d, J = 8.6 Hz, 1H), 6.71 (s,2H), 5.07 (dd, J = 920.5 12.3, 5.4 Hz, 1H), 4.38 (s, 4H), 4.10 (t, J =9.0 Hz, 1H), 3.95 (s, 6H), 3.63 (s, 4H), 3.51 (s, 5H), 3.45-3.39 (m,1H), 3.23-3.04 (m, 4H), 3.01-2.81 (m, 8H), 2.80-2.60 (m, 8H), 2.58-2.50(m, 2H), 2.36- 2.22 (m, 1H), 2.20-2.03 (m, 3H), 2.00-1.76 (m, 6H),1.75-1.58 (m, 3H). D221 LCMS (ESI) m/z: [M + H]+ = 906.5 D222 NA ¹H NMR(400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.15 (s, 2H, FA), 7.84 (d, J = 8.3Hz, 1H), 7.64 (s, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 8.4, 2.3Hz, 1H), 6.67-6.56 (m, 3H), 5.12 (dd, J = 12.9, 5.3 Hz, 1H), 4.39-4.35(m, 1H), 4.25-4.17 (m, 4H), 3.81 (s, 6H), 3.59 (t, J = 4.2 Hz, 2H), 3.50(s, 4H), 3.41-3.38 (m, 3H), 2.94-2.85 (m, 1H), 2.67- 2.57 (m, 7H),2.37-2.25 (m, 5H), 2.18 (s, 2H), 2.10-2.01 (m, 1H), 1.90-1.73 (m, 4H),1.63-1.51 (m, 4H), 1.46-1.39 (m, 2H). D223 LCMS (ESI) m/z: [M + H]+ =881.4 D224 LCMS (ESI) m/z: [M + H]+ = 824.4 D225 LCMS (ESI) m/z: [M +H]+ = 824.4 D226 LCMS (ESI) m/z: [M + H]+ = 906.45 D227 LCMS (ESI) ¹HNMR (300 MHz, Methanol-d4) δ 8.55 (s, 2H, FA), 7.66 (d, J = 8.5 m/z:[M + H]+ = Hz, 1H), 7.61 (s, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.22 (dd, J= 8.7, 2.2 851.6 Hz, 1H), 6.72 (s, 2H), 5.08 (dd, J = 12.3, 5.4 Hz, 1H),4.44-4.34 (m, 4H), 4.13-4.00 (m, 2H), 3.95 (s, 6H), 3.64 (s, 3H), 3.57(t, J = 5.4 Hz, 3H), 3.47-3.34 (m, 4H), 3.22 (t, J = 7.0 Hz, 2H),3.13-2.94 (m, 3H), 2.88 (s, 7H), 2.78-2.62 (m, 4H), 2.24 (s, 2H),2.16-2.07 (m, 1H), 2.03-1.77 (m, 5H), 1.62 (s, 1H), 1.46-1.29 (m, 2H).D228 LCMS (ESI) m/z: [M + H]+ = 810.7 D229 LCMS (ESI) m/z: [M + H]+ =881.6 D230 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.17(s, 2H, FA), 7.69 m/z: [M + H]+ = (d, J = 8.5 Hz, 1H), 7.65 (s, 1H),7.35 (s, 1H), 7.31-7.23 (m, 1H), 892.5 6.82 (d, J = 7.4 Hz, 1H), 6.63(s, 2H), 5.08 (dd, J = 12.8, 5.2 Hz, 1H), 4.22 (s, 2H), 4.03 (q, J = 7.9Hz, 1H), 3.81 (s, 6H), 3.77-3.70 (m, 4H), 3.61 (s, 2H), 3.50 (s, 3H),3.47-3.38 (m, 10H), 2.94-2.76 (m, 3H), 2.60-2.54 (m, 2H), 2.45-2.29 (m,12H), 2.15 (t, J = 10.2 Hz, 2H), 2.08-1.97 (m, 1H), 1.51-1.33 (m, 4H).D231 LCMS (ESI) m/z: [M + H]+ = 809.45 D232 LCMS (ESI) m/z: [M + H]+ =920.45 D233 LCMS (ESI) m/z: [M + H]+ = 868.45 D234 LCMS (ESI) ¹H NMR(400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.18 (s, 1H, FA), 7.67- m/z: [M +H]+ = 7.59 (m, 2H), 6.93-6.85 (m, 2H), 6.77-6.71 (m, 1H), 6.60 (s, 2H),823.45 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 4.23 (s, 2H), 4.14-4.04 (m, 1H),3.79 (s, 6H), 3.59 (s, 2H), 3.53-3.47 (m, 5H), 3.45-3.41 (m, 3H), 3.41(s, 2H), 3.13-3.04 (m, 3H), 2.94-2.83 (m, 1H), 2.74-2.69 (m, 1H),2.62-2.57 (m, 1H), 2.47-2.34 (m, 3H), 2.25 (s, 6H), 2.15 (t, J = 10.9Hz, 1H), 2.05-1.89 (m, 4H), 1.79-1.68 (m, 2H), 1.65-1.56 (m, 2H). D235LCMS (ESI) m/z: [M + H]+ = 852.45 D236 LCMS (ESI) m/z: [M + H]+ = 837.45D237 LCMS (ESI) m/z: [M + H]+ = 838.4 D238 LCMS (ESI) m/z: [M + H]+ =D239 823.45 m/z: [M + H]+ = 824.85 D240 LCMS (ESI) m/z: [M + H]+ = 920.5D241 LCMS (ESI) m/z: [M + H]+ = 795.4 D242 LCMS (ESI) m/z: [M + H]+ =838.45 D243 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.27(s, 2H, FA), 7.68 m/z: [M + H]+ = (d, J = 8.5 Hz, 1H), 7.64 (s, 1H),7.34 (s, 1H), 7.26 (d, J = 8.7 Hz, 1H), 892.45 6.77 (s, 1H), 6.58 (s,2H), 5.08 (dd, J = 12.8, 5.5 Hz, 1H), 4.28 (d, J = 5.9 Hz, 2H),4.02-3.94 (m, 1H), 3.78 (s, 6H), 3.61-3.50 (m, 4H), 3.50-3.42 (m, 12H),2.95-2.85 (m, 2H), 2.79-2.67 (m, 3H), 2.64- 2.56 (m, 3H), 2.40-2.25 (m,4H), 2.14 (s, 6H), 2.05-1.81 (m, 3H), 1.76-1.67 (m, 1H), 1.63-1.47 (m,5H). D244 LCMS (ESI) m/z: [M + H]+ = 824.45 D245 LCMS (ESI) m/z: [M +H]+ = 906.45 D246 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H),9.37 (s, 1H, TFA), m/z: [M + H]+ = 9.04 (s, 1H), 7.69 (t, J = 4.1 Hz,2H), 6.93 (s, 1H, TFA), 6.75 (d, J = 823.45 13.2 Hz, 3H), 6.65 (d, J =8.3 Hz, 1H), 5.06 (dd, J = 12.8, 5.3 Hz, 1H), 4.31-4.09 (m, 4H), 3.89(d, J = 6.6 Hz, 8H), 3.83 (s, 2H), 3.52 (s, 3H), 3.45 (s, 4H), 3.25-2.79(m, 8H), 2.76 (d, J = 4.8 Hz, 6H), 2.66- 2.60 (m, 3H), 2.16 (d, J = 13.7Hz, 2H), 1.95 (dd, J = 34.7, 19.8 Hz, 5H). D247 LCMS (ESI) m/z: [M + H]+= 892.6 D248 LCMS (ESI) m/z: [M + H]+ = 810.4 D249 LCMS (ESI) m/z: [M +H]+ = 796.35 D250 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 2H,FA), 7.90 (d, J = 8.2 Hz, m/z: 1H), 7.67 (s, 1H), 7.50 (d, J = 2.2 Hz,1H), 7.39 (dd, J = 8.3, 2.3 Hz, [M + H]+ = 838.35 1H), 6.78 (s, 2H),6.59 (d, J = 7.1 Hz, 1H), 5.13 (dd, J = 12.9, 5.4 Hz, 1H), 4.48 (s, 2H),4.31 (t, J = 5.7 Hz, 2H), 4.25 (s, 2H), 4.06 (q, J = 7.5 Hz, 1H), 3.88(s, 6H), 3.52 (s, 6H), 3.46-3.39 (m, 2H), 3.11-3.05 (m, 2H), 3.01 (s,6H), 2.93 (s, 2H), 2.92-2.80 (m, 1H), 2.63 (s, 1H), 2.61-2.53 (m, 2H),2.35 (s, 2H), 2.10-2.04 (m, 1H), 1.94-1.83 (m, 2H), 1.70 (t, J = 6.8 Hz,3H), 1.60-1.44 (m, 3H). D251 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ11.12 (s, 1H), 8.17 (s, 1H, FA), 7.83 m/z: (d, J = 8.2 Hz, 1H), 7.63 (s,1H), 7.33-7.25 (m, 2H), 6.65-6.57 (m, [M + H]+ = 878.85 3H), 5.12 (dd, J= 12.8, 5.4 Hz, 1H), 4.98 (q, J = 6.8 Hz, 1H), 4.22 (s, 2H), 3.79 (s,6H), 3.63 (s, 2H), 3.50 (s, 3H), 3.41 (t, J = 5.5 Hz, 3H), 2.95-2.84 (m,3H), 2.64-2.56 (m, 6H), 2.48-2.34 (m, 8H), 2.26- 2.15 (m, 2H), 2.09-2.00(m, 1H), 1.87-1.78 (m, 2H), 1.70-1.55 (m, 6H), 1.42-1.32 (m, 2H),1.31-1.10 (m, 3H). D252 LCMS (ESI) m/z: [M + H]+ = 838.35 D253 LCMS(ESI) ¹H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.17 (s, 1H, FA), 7.83m/z: (d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.35-7.23 (m, 2H), 6.68-6.55 (m,[M + H]⁺ = 864.85. 3H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 5.04-4.93 (m,1H), 4.22 (s, 2H), 3.81 (s, 6H), 3.73 (s, 2H), 3.50 (s, 3H), 3.43-3.41(m, 3H), 3.01- 2.93 (m, 2H), 2.92-2.77 (m, 2H), 2.64-2.56 (m, 6H),2.45-2.26 (m, 7H), 2.15-1.99 (m, 3H), 1.86-1.76 (m, 2H), 1.71-1.53 (m,7H), 1.26-1.08 (m, 2H). D254 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ11.12 (s, 1H), 8.21 (s, 1H, FA), 7.84 m/z: (d, J = 8.3 Hz, 1H), 7.63 (s,1H), 7.34-7.26 (m, 2H), 6.65-6.56 (m, [M + H]+ = 878.65. 3H), 5.12 (dd,J = 12.8, 5.4 Hz, 1H), 5.03 (t, J = 6.9 Hz, 1H), 4.22 (s, 2H), 3.78 (s,6H), 3.53-3.49 (m, 6H), 3.43-3.39 (m, 6H), 2.96- 2.78 (m, 4H), 2.64-2.56(m, 5H), 2.47-2.44 (m, 1H), 2.15-2.00 (m, 4H), 1.92-1.82 (m, 2H),1.67-1.43 (m, 9H). D255 LCMS (ESI) 1H-NMR (400 MHz, DMSO-d6) δ 11.09 (s,1H), 8.15 (s, 1H, FA), 7.69 m/z: (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.35(d, J = 2.2 Hz, 1H), 7.27 (dd, J = [M + H]+ = 835.45. 8.7, 2.3 Hz, 1H),6.69 (s, 2H), 6.61 (q, J = 4.3 Hz, 1H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H),4.22 (s, 2H), 4.04 (s, 2H), 3.86 (s, 6H), 3.51 (s, 3H), 3.48-3.38 (m,7H), 3.10-2.83 (m, 5H), 2.73 (t, J = 7.6 Hz, 1H), 2.64- 2.53 (m, 6H),2.39 (s, 4H), 2.08-1.95 (m, 3H), 1.76 (s, 2H), 1.73- 1.57 (m, 4H). D256LCMS (ESI) ¹H NMR (300 MHz, DMSO) δ 11.08 (s, 1H), 8.20 (d, FA, 2H),7.73- m/z: 7.61 (m, 2H), 7.39-7.18 (m, 2H), 6.60 (d, 3H), 5.07 (dd, 1H),4.22 (s, [M + H]+ = 809. 2H), 3.80 (s, 7H), 3.63 (d, 3H), 3.50 (s, 3H),3.42 (d, 6H), 2.98-2.80 (m, 3H), 2.60 (d, 4H), 2.51-2.39 (m, 5H),2.22-2.12 (m, 4H), 2.16- 1.95 (m, 1H), 1.69 (d, 2H), 1.60-1.45 (m, 1H),1.22-1.05 (m, 2H); D257 LCMS (ESI) ¹H NMR (400 MHz, Methanol-d4) δ 8.49(s, 3H, FA), 7.81 (d, J = 8.4 m/z: Hz, 1H), 7.56-7.48 (m, 2H), 7.39 (d,J = 8.6 Hz, 1H), 6.64 (s, 2H), [M + H]+ = 809.50. 5.12 (dd, J = 12.6,5.4 Hz, 1H), 4.35 (s, 2H), 4.10-4.02 (m, 3H), 3.90 (s, 6H), 3.89-3.85(m, 3H), 3.84-3.62 (m, 9H), 3.55-3.48 (m, 3H), 3.08-3.01 (m, 1H),2.98-2.83 (m, 2H), 2.78 (s, 3H), 2.76-2.70 (m, 2H), 2.64-2.57 (m, 2H),2.44 (s, 1H), 2.17-1.98 (m, 4H), 1.39- 1.27 (m, 2H). D258 LCMS (ESI) ¹HNMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 (s, 1H, FA), 7.79 m/z: (d,J = 8.3 Hz, 1H), 7.56 (d, J = 30.9 Hz, 2H), 7.47-7.31 (m, 1H), [M + H]+= 795.40. 6.61 (d, J = 5.4 Hz, 3H), 5.10 (dd, J = 13.0, 5.4 Hz, 1H),4.21 (s, 2H), 3.91 (d, J = 8.9 Hz, 1H), 3.81 (s, 10H), 3.76-3.57 (m,12H), 3.40 (t, J = 5.6 Hz, 4H), 3.26 (t, J = 10.7 Hz, 2H), 2.98-2.82 (m,1H), 2.71 (s, 1H), 2.66-2.54 (m, 5H), 2.28-2.20 (m, 1H), 2.09-1.98 (m,1H), 1.84-1.79 (s, 1H). D259 LCMS (ESI) ¹H NMR (300 MHz, Methanol-d4) δ8.48 (s, 1H, FA), 7.84 (d, J = 8.3 m/z: [M + H]+ = Hz, 1H), 7.60 (s,1H), 7.46 (s, 1H), 7.40-7.34 (m, 1H), 6.72 (s, 2H), 854.4 5.13 (dd, J =12.4, 5.4 Hz, 1H), 4.44-4.35 (m, 6H), 4.19-4.09 (m, 1H), 3.95 (s, 6H),3.69-3.48 (m, 8H), 3.43-3.38 (m, 1H), 3.18- 3.11 (m, 2H), 2.92-2.72 (m,13H), 2.65 (s, 2H), 2.21-2.10 (m, 1H), 1.98 (dd, J = 12.8, 7.2 Hz, 1H),1.82-1.71 (m, 4H), 1.58-1.47 (m, 1H). D260 LCMS (ESI) m/z: [M + H]+ =795.4 D261 LCMS (ESI) m/z: [M + H]+ = 809.45 D262 LCMS (ESI) ¹H NMR (400MHz, DMSO-d6) δ 8.43 (s, 2H, FA), 7.90 (d, J = 8.4 Hz, m/z: [M + H]+ =1H), 7.68 (s, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.39 (dd, J = 8.4, 2.3 Hz,824.4 1H), 6.88 (d, J = 6.7 Hz, 1H), 6.77 (s, 2H), 5.14 (dd, J = 12.8,5.4 Hz, 1H), 4.48 (s, 2H), 4.31 (t, J = 5.2 Hz, 4H), 4.25 (s, 2H), 4.13(dq, J = 16.8, 8.2 Hz, 1H), 3.88 (s, 6H), 3.52 (s, 6H), 3.42 (t, J = 4.7Hz, 2H), 3.01 (s, 6H), 2.96-2.84 (m, 4H), 2.63 (d, J = 3.8 Hz, 1H),2.61-2.53 (m, 3H), 2.40-2.33 (m, 1H), 2.27-1.96 (m, 6H), 1.87-1.82 (m,1H), 1.81-1.74 (m, 1H). D263 LCMS (ESI) m/z: [M + H]+ = 810.45 D264 LCMS(ESI) m/z: [M + H]+ = 796.7 D265 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6with a drop of D₂O) δ 8.40 (s, 2H, FA), m/z: [M + H]+ = 7.88 (d, J = 8.3Hz, 1H), 7.66 (s, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.39 838.45 (dd, J =8.4, 2.3 Hz, 1H), 6.74 (s, 2H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.47(s, 2H), 4.30 (t, J = 6.1 Hz, 2H), 4.23 (s, 2H), 3.86 (s, 6H), 3.55-3.48 (m, 5H), 3.41 (s, 2H), 3.25 (s, 1H), 3.07-2.97 (m, 9H), 2.96- 2.81(m, 3H), 2.75-2.70 (m, 1H), 2.66-2.55 (m, 5H), 2.34 (s, 1H), 2.24-2.14(m, 1H), 2.09-1.94 (m, 3H), 1.52-1.42 (m, 2H), 1.03- 0.97 (m, 1H). D266LCMS (ESI) m/z: [M + H]+ = 824.4 D267 LCMS (ESI) m/z: [M + H]+ = 838.4D268 LCMS (ESI) m/z: [M + H]+ = 810.7 D269 LCMS (ESI) ¹H NMR (400 MHz,Methanol-d4) δ 8.51 (s, 2H, FA), 7.81 (d, J = 8.2 m/z: [M + H]+ = Hz,1H), 7.60 (s, 1H), 7.46 (s, 1H), 7.37 (d, J = 8.2 Hz, 1H), 6.71 (s,824.45 2H), 5.12 (dd, J = 12.4, 5.4 Hz, 1H), 4.49 (s, 2H), 4.37 (d, J =2.8 Hz, 4H), 3.95 (s, 6H), 3.63 (s, 3H), 3.58-3.52 (m, 2H), 3.37 (s,2H), 3.27 (d, J = 7.3 Hz, 2H), 3.15 (s, 4H), 2.88 (s, 7H), 2.80-2.58 (m,4H), 2.17-2.07 (m, 1H), 1.97-1.55 (m, 4H), 1.18-1.06 (m, 1H), 0.70- 0.60(m, 1H), 0.37 (t, J = 5.1 Hz, 1H). D270 LCMS (ESI) m/z: [M + H]+ = 810.4D271 LCMS (ESI) m/z: [M + H]+ = 810.45 D272 LCMS (ESI) m/z: [M + H]+ =824.4 D273 LCMS (ESI) m/z: [M + H]+ = 810.4 D274 LCMS (ESI) ¹H NMR (400MHz, DMSO-d6) δ 11.12 (s, 1H), 8.18 (s, 2H, FA), 7.84 m/z: [M + H]+ =(d, J = 8.3 Hz, 1H), 7.64 (s, 1H), 7.46 (dd, J = 4.0, 2.2 Hz, 1H), 7.37796.35 (dt, J = 8.3, 2.3 Hz, 1H), 6.63 (s, 2H), 6.58 (d, J = 4.9 Hz,1H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.26 (d, J = 11.7 Hz, 4H), 3.89(s, 1H), 3.80 (d, J = 1.9 Hz, 6H), 3.74-3.54 (m, 4H), 3.50 (s, 3H), 3.44(d, J = 5.7 Hz, 2H), 3.18-3.10 (m, 2H), 3.03-2.98 (m, 1H), 2.92-2.84 (m,3H), 2.74-2.69 (m, 1H), 2.32 (s, 5H), 2.22 (d, J = 13.6 Hz, 2H), 2.09-2.04 (s, 2H), 1.80 (t, J = 11.3 Hz, 1H), 1.74-1.61 (m, 2H), 1.46 (d, J =10.2 Hz, 1H). LCMS (ESI) m/z: [M + H]+ = 796.35 D275 LCMS (ESI) ¹H NMR(400 MHz, Methanol-d4) δ 8.56 (br s, 1H, FA), 7.82 (d, J = m/z: 8.3 Hz,1H), 7.58 (s, 1H), 7.30 (s, 1H), 7.25 (dd, J = 8.2, 2.2 Hz, 1H), [M +H]+ = 864.45. 6.72 (s, 2H), 5.12 (dd, J = 12.7, 5.4 Hz, 1H), 4.97 (t, J= 6.6 Hz, 1H), 4.47 (s, 2H), 4.36 (s, 2H), 4.25 (t, J = 9.5 Hz, 2H),4.01-3.90 (m, 8H), 3.64 (s, 3H), 3.60-3.49 (m, 5H), 3.47-3.42 (m, 1H),3.23-3.17 (m, 1H), 2.95-2.82 (m, 3H), 2.80-2.67 (m, 5H), 2.64-2.54 (m,4H), 2.18-2.10 (m, 1H), 2.03 (dd, J = 12.7, 6.2 Hz, 2H), 1.80-1.60 (m,4H). D276 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.84 (d,J = 8.3 Hz, m/z: 1H), 7.70 (t, J = 5.8 Hz, 1H), 7.62 (s, 1H), 7.44 (d, J= 2.3 Hz, 1H), [M + H]+ = 852.39. 7.36 (dd, J = 8.3, 2.3 Hz, 1H),6.62-6.57 (m, 1H), 6.56 (s, 2H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.19(dd, J = 13.0, 6.6 Hz, 4H), 3.77 (s, 6H), 3.50 (s, 3H), 3.44 (s, 2H),3.40 (t, J = 5.5 Hz, 2H), 3.40-3.35 (m, 2H), 3.07 (q, J = 6.5 Hz, 2H),2.95-2.84 (m, 1H), 2.63-2.54 (m, 5H), 2.09-1.97 (m, 4H), 1.90 (s, 6H),1.81-1.71 (m, 2H), 1.54-1.35 (m, 4H). D277 LCMS (ESI) ¹H NMR (300 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.23 (s, 1H, FA), 7.84 m/z: (d, J = 8.3 Hz,1H), 7.61 (s, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.35 (dd, J = [M + H]+ =820.55. 8.3, 2.3 Hz, 1H), 7.25 (t, J = 5.8 Hz, 1H), 6.64-6.54 (m, 3H),5.13 (dd, J = 12.9, 5.4 Hz, 1H), 4.25-4.15 (m, 4H), 4.02-3.85 (m, 2H),3.77 (s, 6H), 3.57 (s, 2H), 3.49 (s, 3H), 3.43-3.38 (m, 6H), 3.11 (q, J= 6.5 Hz, 2H), 2.96-2.82 (m, 1H), 2.66-2.52 (m, 6H), 2.10-1.99 (m, 1H),1.97-1.85 (m, 2H). D278 LCMS (ESI) ¹H NMR (400 MHz, Methanol-d4) δ 8.48(s, 1H, FA), 7.80 (d, J = 8.3 m/z: Hz, 1H), 7.55 (s, 1H), 7.40 (d, J =2.3 Hz, 1H), 7.32 (dd, J = 8.4, 2.3 [M + H]+ = 834.15 Hz, 1H), 6.63 (s,2H), 5.11 (dd, J = 12.5, 5.4 Hz, 1H), 4.35 (s, 2H), 4.20 (t, J = 6.2 Hz,2H), 4.16-4.06 (m, 1H), 4.02 (s, 2H), 3.88 (s, 6H), 3.88-3.83 (m, 4H),3.63 (s, 3H), 3.53 (t, J = 5.6 Hz, 2H), 3.14 (t, J = 6.9 Hz, 2H),2.95-2.83 (m, 1H), 2.80-2.67 (m, 5H), 2.65-2.60 (m, 2H), 2.18-2.09 (m,1H), 1.97-1.86 (m, 2H), 1.80-1.67 (m, 2H). D279 LCMS (ESI) ¹H NMR (400MHz, DMSO-d6) δ 11.12 (s, 1H), 7.86 (d, J = 8.3 Hz, m/z: 1H), 7.61 (s,1H), 7.51 (s, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.37 (dd, J = [M + H]+ =806.45. 8.3, 2.3 Hz, 1H), 6.62-6.53 (m, 3H), 5.13 (dd, J = 12.9, 5.3 Hz,1H), 4.24-4.16 (m, 4H), 4.04 (s, 1H), 3.78 (s, 6H), 3.59 (s, 2H), 3.49(s, 3H), 3.47-3.36 (m, 7H), 3.31 (s, 1H), 2.95-2.83 (m, 1H), 2.64- 2.53(m, 7H), 2.10-2.02 (m, 1H). D280 LCMS (ESI) ¹H NMR (300 MHz, DMSO-d6) δ11.12 (s, 1H), 7.83 (dd, J = 8.5, 7.2 m/z: Hz, 1H), 7.62 (s, 1H), 7.53(d, J = 8.5 Hz, 1H), 7.47 (d, J = 7.2 Hz, [M + H]+ = 820.60. 1H),6.75-6.58 (m, 3H), 5.09 (dd, J = 12.8, 5.4 Hz, 1H), 4.28-4.19 (m, 4H),3.96-3.61 (m, 8H), 3.50 (s, 3H), 3.40 (t, J = 5.5 Hz, 2H), 3.38 (s, 6H),3.24-3.14 (m, 2H), 2.97-2.82 (m, 1H), 2.64-2.54 (m, 6H), 2.09-1.88 (m,3H). D281 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.08(s, 1H, TFA), m/z: 7.83 (dd, J = 8.5, 7.2 Hz, 1H), 7.69 (s, 1H), 7.64(s, 1H), 7.53 (d, J = [M + H]+ = 834.10 8.5 Hz, 1H), 7.47 (d, J = 7.3Hz, 1H), 6.71 (s, 2H), 6.61 (q, J = 4.3 Hz, 1H), 5.09 (dd, J = 12.7, 5.5Hz, 1H), 4.66-4.29 (m, 5H), 4.26-4.14 (m, 5H), 3.86 (s, 6H), 3.51 (s,3H), 3.44-3.39 (m, 4H), 3.11-3.01 (m, 2H), 2.94-2.81 (m, 1H), 2.64-2.53(m, 6H), 2.07-1.98 (m, 1H), 1.85-1.76 (m, 2H), 1.70-1.60 (m, 2H). D282LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.84 (t, J = 7.8Hz, m/z: [M + H]+ = 1H), 7.62 (s, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.50(d, J = 7.2 Hz, 1H), 806.60. 6.69-6.53 (m, 3H), 5.11 (dd, J = 12.8, 5.4Hz, 1H), 4.49-4.00 (m, 7H), 3.79 (s, 7H), 3.56-3.47 (m, 4H), 3.44-3.37(m, 5H), 2.94- 2.83 (m, 1H), 2.59 (d, J = 4.2 Hz, 4H), 2.57-2.53 (m,4H), 2.07- 1.98 (m, 1H). D283 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ11.11 (s, 1H), 7.82 (dd, J = 8.5, 7.3 m/z: Hz, 1H), 7.69 (t, J = 5.8 Hz,1H), 7.62 (s, 1H), 7.53 (d, J = 8.6 Hz, 1H), [M + H]+ = 852.39. 7.45 (d,J = 7.2 Hz, 1H), 6.59 (d, J = 4.4 Hz, 1H), 6.56 (s, 2H), 5.08 (dd, J =12.9, 5.4 Hz, 1H), 4.24-4.17 (m, 4H), 3.77 (s, 6H), 3.50 (s, 3H), 3.44(s, 2H), 3.40 (t, J = 5.6 Hz, 2H), 3.37 (s, 2H), 3.11-3.03 (m, 2H),2.93-2.81 (m, 1H), 2.61-2.55 (m, 5H), 2.07-1.98 (m, 4H), 1.90 (s, 6H),1.81-1.73 (m, 2H), 1.54-1.38 (m, 4H). D284 LCMS (ESI) ¹H NMR (400 MHz,DMSO-d6) δ 11.09 (s, 1H), 8.15 (s, 1H, FA), 7.67 m/z: (d, J = 8.5 Hz,1H), 7.63 (s, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = [M + H]+ =813.45 8.7, 2.3 Hz, 1H), 6.61 (d, J = 6.9 Hz, 3H), 5.07 (dd, J = 12.9,5.4 Hz, 1H), 4.21 (s, 2H), 3.84-3.77 (m, 7H), 3.71 (s, 2H), 3.64-3.53(m, 5H), 3.52-3.46 (m, 4H), 3.43-3.38 (m, 7H), 2.95-2.83 (m, 1H), 2.72(s, 2H), 2.60-2.53 (m, 9H), 2.28 (s, 3H), 2.06-1.97 (m, 1H). D285 LCMS(ESI) ¹H NMR (300 MHz, Methanol-d4) δ 8.56 (br s, 1.7H, FA), 7.55 (s,1H), m/z: 7.24 (t, J = 7.7 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.91 (d, J= 7.9 Hz, [M − H]+ = 774.37. 1H), 6.71 (s, 2H), 5.19 (dd, J = 13.4, 5.1Hz, 1H), 4.39-4.27 (m, 5H), 4.09-3.98 (m, 2H), 3.94 (s, 6H), 3.67-3.50(m, 14H), 3.40 (t, J = 5.4 Hz, 2H), 3.04-2.91 (m, 2H), 2.85 (s, 6H),2.61 (s, 2H), 2.53-2.39 (m, 1H), 2.24-2.12 (m, 1H). D286 LCMS (ESI) ¹HNMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.18 (s, 1.0H, FA), m/z: 7.83(d, J = 8.3 Hz, 1H), 7.68-7.62 (m, 2H), 7.43 (d, J = 2.3 Hz, 1H), [M +H]+ = 866.30. 7.35 (dd, J = 8.3, 2.3 Hz, 1H), 6.62-6.56 (m, 3H), 5.12(dd, J = 12.9, 5.4 Hz, 1H), 4.25-4.13 (m, 4H), 3.78 (s, 6H), 3.54 (s,2H), 3.50 (s, 3H), 3.42-3.38 (m, 3H), 3.05 (q, J = 6.6 Hz, 2H),2.94-2.84 (m, 1H), 2.64-2.53 (m, 6H), 2.48 (s, 2H), 2.11 (s, 3H),2.08-2.01 (m, 1H), 1.85 (s, 6H), 1.80-1.71 (m, 2H), 1.51-1.35 (m, 4H).D287 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.16 (s,0.7H, FA), m/z: 7.68 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H), 7.35 (d, J = 2.3Hz, 1H), 7.26 [M + H]+ = 874.35. (dd, J = 8.6, 2.3 Hz, 1H), 7.08 (t, J =5.8 Hz, 1H), 6.58 (s, 3H), 5.07 (dd, J = 12.9, 5.3 Hz, 1H), 4.21 (s,2H), 4.07-3.95 (m, 1H), 3.78 (s, 6H), 3.58 (s, 2H), 3.49 (s, 3H),3.47-3.34 (m, 14H), 3.08 (q, J = 6.5 Hz, 2H), 2.94-2.82 (m, 1H), 2.59(d, J = 4.2 Hz, 5H), 2.54 (s, 2H), 2.42 (t, J = 6.7 Hz, 2H), 2.07-1.99(m, 1H). D288 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.19(s, 0.9H, FA), m/z: 7.81 (dd, J = 8.6, 7.3 Hz, 1H), 7.68-7.61 (m, 2H),7.52 (d, J = 8.6 Hz, [M + H]+ = 866.25. 1H), 7.45 (d, J = 7.2 Hz, 1H),6.64-6.54 (m, 3H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 4.26-4.13 (m, 4H),3.78 (s, 6H), 3.55-3.47 (m, 6H), 3.40 (t, J = 5.5 Hz, 2H), 3.08-3.01 (m,2H), 2.93-2.82 (m, 1H), 2.63- 2.52 (m, 6H), 2.47 (s, 2H), 2.10 (s, 3H),2.06-1.99 (m, 1H), 1.84 (s, 6H), 1.81-1.73 (m, 2H), 1.51-1.39 (m, 4H).D289 LCMS (ESI) ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.19 (s,0.9H, FA), m/z: 7.83 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.44 (d, J = 2.3Hz, 1H), 7.36 (d, [M + H]+ = 854.70. J = 8.4 Hz, 1H), 6.58 (s, 3H), 5.12(dd, J = 12.9, 5.4 Hz, 1H), 4.33- 4.26 (m, 2H), 4.21 (s, 2H), 3.97-3.89(m, 1H), 3.76 (s, 8H), 3.70- 3.67 (m, 2H), 3.59 (s, 3H), 3.49 (s, 4H),2.95-2.76 (m, 5H), 2.63- 2.52 (m, 10H), 2.29-2.19 (m, 1H), 2.18-2.10 (m,1H), 2.09-1.99 (m, 1H), 1.52-1.28 (m, 2H). D290 LCMS (ESI) ¹H NMR (400MHz, DMSO-d6, D2O) δ 8.53 (t, J = 5.8 Hz, TFA salt), m/z: 7.84 (d, J =8.3 Hz, 1H), 7.66 (s, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.40 [M + H]+ =815.50. (dd, J = 8.3, 2.3 Hz, 1H), 6.68 (s, 2H), 5.11 (dd, J = 12.9, 5.4Hz, 1H), 4.77 (s, 2H), 4.22 (d, J = 4.7 Hz, 4H), 3.86 (s, 6H), 3.58-3.52(m, 2H), 3.50 (s, 3H), 3.44-3.14 (m, 8H), 2.94-2.83 (m, 4H), 2.75 (s,6H), 2.65-2.53 (m, 4H), 2.08-1.96 (m, 1H). D291 LCMS (ESI) 1H-NMR (400MHz, DMSO-d6) δ 11.01 (s, 1H), 8.31 (t, J = 5.3 Hz, m/z: 1H), 8.22 (s,0.8H, FA), 7.64 (s, 1H), 7.48 (t, J = 8.1 Hz, 1H), 6.68- [M + H]+ =797.55. 6.59 (m, 4H), 6.49 (d, J = 8.3 Hz, 1H), 5.18 (dd, J = 11.5, 5.6Hz, 1H), 4.22 (s, 2H), 3.79 (s, 6H), 3.62 (s, 2H), 3.50 (s, 3H), 3.40(t, J = 5.5 Hz, 2H), 3.14 (q, J = 6.6 Hz, 2H), 3.03 (q, J = 6.5 Hz, 2H),2.90-2.76 (m, 1H), 2.70-2.58 (m, 2H), 2.58-2.52 (m, 5H), 2.27 (s, 6H),2.20- 2.08 (m, 1H), 1.65-1.54 (m, 2H), 1.44-1.38 (m, 2H), 1.37-1.18 (m,8H). D292 LCMS (ESI) 1H-NMR (400 MHz, Methanol-d4) δ 8.55 (brs, 0.9H,FA), 7.53 (s, 1H), m/z: 7.43 (t, J = 8.1 Hz, 1H), 6.70-6.63 (m, 3H),6.51 (d, J = 8.3 Hz, 1H), [M + H]+ = 801.50. 5.20-5.13 (m, 1H),4.41-4.25 (m, 4H), 3.94 (s, 6H), 3.82-3.77 (m, 2H), 3.68 (s, 4H),3.62-3.57 (m, 5H), 3.56-3.35 (m, 6H), 2.93- 2.79 (m, 8H), 2.78-2.69 (m,1H), 2.62 (s, 3H), 2.58-2.50 (m, 2H), 2.23-2.14 (m, 1H). D293 764.3 ¹HNMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.41 (d, J = 8.6 Hz, 1H),6.75-6.62 (m, 4H), 5.06 (dd, J = 13.2, 5.0 Hz, 1H), 4.35 (t, J = 18.7Hz, 4H), 4.27-4.16 (m, 3H), 4.11-3.98 (m, 3H), 3.88 (s, 6H), 3.75- 3.62(m, 5H), 3.53 (s, 3H), 3.31-3.12 (m, 3H), 3.05-2.82 (m, 8H), 2.81-2.73(m, 1H), 2.70-2.56 (m, 3H), 2.42-2.32 (m, 1H), 2.18- 2.05 (m, 2H),2.04-1.84 (m, 3H). D294 866.45 ¹H NMR (400 MHz, DMSO-d6) δ 11.13 (s,1H), 8.20 (s, 0.9H, FA), 7.81 (dd, J = 8.5, 7.2 Hz, 1H), 7.64 (t, J =5.8 Hz, 1H), 7.58-7.49 (m, 2H), 7.44 (d, J = 7.2 Hz, 1H), 6.58 (s, 2H),6.54 (q, J = 4.3 Hz, 1H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 4.26 (s, 2H),4.20 (t, J = 6.4 Hz, 2H), 3.79 (s, 6H), 3.56-3.49 (m, 4H), 3.47 (s, 3H),3.05 (q, J = 6.4 Hz, 2H), 2.88 (ddd, J = 17.3, 14.1, 5.4 Hz, 1H),2.63-2.55 (m, 1H), 2.55- 2.51 (m, 4H), 2.50-2.46 (m, 4H), 2.11 (s, 3H),2.07-1.99 (m, 1H), 1.85 (s, 6H), 1.77 (t, J = 6.9 Hz, 2H), 1.50-1.39 (m,4H). D295 854.7 ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.15 (s,0.7H, FA), 7.83 (d, J = 8.3 Hz, 1H), 7.56 (s, 1H), 7.45 (d, J = 2.2 Hz,1H), 7.36 (dd, J = 8.3, 2.3 Hz, 1H), 6.61 (s, 2H), 6.55 (q, J = 4.4 Hz,1H), 5.12 (dd, J = 12.9, 5.4 Hz, 1H), 4.31-4.27 (m, 2H), 4.25 (s, 2H),3.94- 3.88 (m, 1H), 3.79 (s, 8H), 3.75 (s, 2H), 3.72-3.68 (m, 3H), 3.47(s, 4H), 3.10-3.01 (m, 2H), 2.99-2.81 (m, 3H), 2.69-2.52 (m, 10H),2.41-2.32 (m, 1H), 2.31-2.21 (m, 1H), 2.08-1.97 (m, 1H), 1.64- 1.39 (m,2H). D296 813.45 ¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.16 (s,1.1H, FA), 7.67 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.34 (d, J = 2.3 Hz,1H), 7.25 (dd, J = 8.7, 2.3 Hz, 1H), 6.63 (s, 2H), 6.54 (d, J = 4.5 Hz,1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.27 (s, 2H), 3.82 (s, 6H), 3.73(s, 2H), 3.63- 3.55 (m, 4H), 3.52 (t, J = 5.9 Hz, 2H), 3.46 (s, 3H),3.45-3.38 (m, 8H), 2.94-2.84 (m, 1H), 2.75 (s, 2H), 2.64-2.54 (m, 9H),2.35- 2.25 (m, 3H), 2.08-1.97 (m, 1H). D297 802.55 ¹H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.19 (s, 0.8H, FA), 7.82-7.72 (m, 2H), 7.54(s, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 6.57 (s,2H), 6.56-6.51 (m, 1H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 4.37-4.29 (m,2H), 4.25 (s, 2H), 3.85-3.77 (m, 8H), 3.59 (t, J = 5.7 Hz, 2H),3.54-3.50 (m, 4H), 3.46 (s, 3H), 3.34 (q, J = 5.9 Hz, 4H), 2.94 (s, 2H),2.91-2.83 (m, 1H), 2.62-2.52 (m, 5H), 2.10 (s, 3H), 2.05-1.96 (m, 1H).D298 827.5 1H-NMR (400 MHz, Methanol-d4) δ 8.47 (brs, 1.4H, FA), 7.69(d, J = 8.5 Hz, 1H), 7.50 (s, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.24 (dd, J= 8.6, 2.3 Hz, 1H), 6.77 (s, 2H), 5.08 (dd, J = 12.4, 5.5 Hz, 1H), 4.50(s, 2H), 4.09 (s, 2H), 3.97 (s, 6H), 3.92-3.87 (m, 2H), 3.76 (t, J = 5.2Hz, 2H), 3.61 (s, 3H), 3.51-3.45 (m, 8H), 2.90-2.86 (m, 4H), 2.83 (s,6H), 2.79-2.71 (m, 10H), 2.17-2.07 (m, 1H). D299 809.94 ¹H NMR (400 MHz,DMSO-d6) δ 11.04 (s, 1H), 8.13 (s, 2H), 7.87 (s, 1H), 7.65 (d, J = 8.5Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 8.7, 2.3 Hz, 1H), 6.68(s, 2H), 6.33 (d, J = 4.5 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.81(s, 5H), 3.65 (d, J = 3.1 Hz, 2H), 3.52 (s, 3H), 3.39 (d, J = 5.4 Hz,4H), 3.15 (s, 2H), 2.97-2.78 (m, 3H), 2.58 (d, J = 4.3 Hz, 3H), 2.00(dd, J = 9.2, 4.2 Hz, 1H), 1.64 (d, J = 12.6 Hz, 2H), 1.35 (s, 1H). D300738.82 ¹H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.14 (s, 1H), 7.85 (d,J = 11.1 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 6.70-6.56 (m, 3H), 5.02 (dd,J = 12.9, 5.4 Hz, 1H), 4.68-4.54 (m, 2H), 4.38 (s, 2H), 3.80 (s, 6H),3.73 (d, J = 19.6 Hz, 4H), 3.52 (s, 3H), 3.47 (s, 2H), 2.93-2.74 (m,1H), 2.58 (dd, J = 4.4, 2.9 Hz, 4H), 2.37 (s, 4H), 2.05-1.91 (m, 1H),1.69 (s, 4H). D301 749.15 ¹H NMR (400 MHz, Methanol-d4) δ 7.41 (d, J =7.8 Hz, 2H), 6.88 (d, J = 2.2 Hz, 1H), 6.80 (dd, J = 8.2, 2.2 Hz, 1H),6.70 (s, 2H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.51 (s, 2H), 4.47-4.20(m, 4H), 4.15 (s, 2H), 3.95 (s, 6H), 3.77 (s, 4H), 3.61 (s, 3H),3.55-3.35 (m, 5H), 3.15 (s, 1H), 3.29-3.01 (m, 1H), 2.98-2.85 (m, 1H),2.80 (d, J = 17.6 Hz, 1H), 2.60 (t, J = 6.4 Hz, 2H), 2.51-2.47 (m, 3H),2.25-2.04 (m, 5H), 1.85-1.79 (m, 2H), 1.72-1.67 (m, 2H). D302 737.4 1HNMR (400 MHz, Methanol-d4) δ 8.33 (s, 2H, FA), 7.91 (s, 1H), 7.39 (d, J= 8.2 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.81-6.74 (m, 3H), 5.23 (t, J =3.4 Hz, 2H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 5.07 (t, J = 3.4 Hz, 2H),4.45 (s, 2H), 4.42 (d, J = 16.5 Hz, 1H), 4.36 (d, J = 16.5 Hz, 1H), 4.22(t, J = 9.4 Hz, 2H), 3.98 (s, 6H), 3.95 (d, J = 10.0 Hz, 2H), 3.71 (s,3H), 3.68 (s, 4H), 3.20-3.10 (m, 1H), 2.98-2.86 (m, 1H), 2.84-2.69 (m,3H), 2.61-2.42 (m, 5H), 2.23-2.13 (m, 1H), 1.94- 1.90 (m, 4H). DD1 LCMS(ESI) ¹H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H, FA), 7.55 (s, 1H),7.49 m/z: (td, J = 8.6, 5.9 Hz, 1H), 7.28-7.20 (m, 1H), 7.19-7.12 (m,1H), [M + H]+ = 878.5. 6.63 (s, 2H), 4.36 (s, 2H), 3.96-3.82 (m, 8H),3.64 (s, 3H), 3.59-3.49 (m, 4H), 3.31-3.24(m, 2H), 2.94-2.74 (m, 8H),2.69-2.45 (m, 7H), 1.79 (d, J = 10.9 Hz, 2H), 1.62-1.46 (m, 5H).

Example 67—Preparation of Compounds D303-D375

In analogy to the procedures described in the examples above, compoundsD303-D375 were prepared using the appropriate starting materials

Compound No. LCMS ¹H NMR D303 669.2 ¹H NMR (400 MHz, DMSO-d6) δ 11.07(s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.60 (s, 1H), 6.82 (d, J = 2.1 Hz,1H), 6.73-6.66 (m, 1H), 6.63-6.53 (m, 3H), 5.06 (dd, J = 12.9, 5.4 Hz,1H), 4.44-4.36 (m, 3H), 4.20 (s, 2H), 4.16 (s, 2H), 3.73 (s, 6H), 3.48(s, 3H), 3.42-3.35 (m, 2H), 2.95-2.81 (m, 1H), 2.63-2.57 (m, 4H),2.57-2.51 (m, 3H), 2.07-1.96 (m, 1H). D304 752.45 ¹H NMR (300 MHz,DMSO-d6) δ 10.97 (s, 1H), 7.65 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 6.69(d, J = 7.5 Hz, 2H), 6.61 (d, J = 5.1 Hz, 3H), 5.08 (dd, J = 13.2, 5.1Hz, 1H), 4.39-4.11 (m, 4H), 3.81 (s, 6H), 3.79-3.53 (m, 4H), 3.54-3.44(m, 5H), 3.47-3.36 (m, 3H), 3.00-2.80 (m, 1H), 2.72-2.51 (m, 6H),2.50-2.10 (m, 4H), 2.05-1.61 (m, 4H), 0.95 (d, J = 6.7 Hz, 3H). D305823.45 ¹H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H, FA), 7.62 (s, 1H), 7.42(d, J = 8.4 Hz, 1H), 7.26 (dd, J = 8.4, 2.4 Hz, 1H), 7.16 (d, J = 2.3Hz, 1H), 6.67-6.58 (m, 2H), 6.54 (s, 1H), 5.16 (dd, J = 13.5, 5.1 Hz,1H), 4.37-4.16 (m, 4H), 3.84-3.70 (m, 10H), 3.50 (s, 3H), 3.40 (t, J =5.7 Hz, 2H), 3.31 (s, 3H), 3.07-2.92 (m, 5H), 2.82-2.66 (m, 8H),2.63-2.58 (m, 4H), 2.38 (dd, 2H), 2.05-1.93 (m, 1H), 1.75 (d, J = 12.5Hz, 2H), 1.48 (s, 3H), 1.35-1.12 (m, 3H). D306 774.4 ¹H NMR (300 MHz,DMSO-d6) δ 10.98 (s, 1H), 7.65 (s, 1H), 7.42 (d, J = 8.6 Hz, 1H),6.75-6.65 (m, 4H), 6.61 (s, 1H), 5.08 (dd, J = 13.3, 5.0 Hz, 1H),4.38-4.15 (m, 5H), 3.92 (s, 3H), 3.86 (s, 7H), 3.75 (s, 3H), 3.51 (s,3H), 2.98-2.83 (m, 2H), 2.60 (s, 7H), 2.43-2.34 (m, 3H), 2.25-2.07 (m,2H), 2.02-1.92 (m, 1H). D307 693.2 ¹H NMR (300 MHz, DMSO-d6) δ 10.97 (s,1H), 7.65 (s, 1H), 7.36 (d, J = 9.2 Hz, 1H), 7.17-7.07 (m, 3H),6.65-6.60 (m, 2H), 6.23-5.73 (m, 1H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H),4.50 (s, 2H), 4.36-4.12 (m, 4H), 3.83 (s, 6H), 3.49 (s, 3H), 3.43 (d, J= 5.0 Hz, 4H), 2.90 (s, 4H), 2.62 (s, 2H), 2.44- 2.29 (m, 2H), 1.98 (d,J = 12.6 Hz, 1H). D308 738.45 ¹H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H),8.18 (s, 1H, FA), 7.65 (s, 1H), 7.37 (d, J = 8.1 Hz, 1H), 6.77-6.65 (m,2H), 6.63-6.53 (m, 3H), 5.08 (m, J = 13.3, 5.1 Hz, 1H), 4.39-4.12 (m,4H), 3.79 (s, 6H), 3.57 (s, 4H), 3.50 (d, J = 4.1 Hz, 4H), 3.41 (m, J =4.9 Hz, 4H), 2.91 (m, J = 17.6, 13.6, 5.3 Hz, 1H), 2.59 (d, J = 4.2 Hz,6H), 2.44-2.33 (m, 4H), 2.03- 1.95 (m, 1H), 1.71 (m, J = 5.3 Hz, 4H).D309 837.6 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.63 (s, 1H), 7.42(d, J = 8.5 Hz, 1H), 7.26 (dd, J = 8.5, 2.4 Hz, 1H), 7.15 (d, J = 2.3Hz, 1H), 6.76- 6.50 (m, 3H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.39-4.14(m, 4H), 3.98- 3.66 (m, 8H), 3.50 (s, 3H), 3.45-3.38 (m, 2H), 3.33-3.26(m, 4H), 3.00- 2.82 (m, 2H), 2.81-2.64 (m, 3H), 2.64-2.56 (m, 5H),2.56-2.52 (m, 2H), 2.49-2.27 (m, 3H), 2.20 (s, 1H), 2.06-1.90 (m, 1H),1.83-1.67 (m, 2H), 1.62-1.35 (m, 5H), 1.35-0.94 (m, 6H). D310 835.5 ¹HNMR (400 MHz, Methanol-d4) δ 7.68-7.61 (m, 1H), 7.54 (s, 1H), 7.10 (d, J= 8.0 Hz, 2H), 6.61 (s, 2H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.63 (s,1H), 4.49-4.38 (m, 2H), 4.36 (s, 2H), 4.22 (s, 1H), 3.97 (d, J = 12.8Hz, 2H), 3.87 (s, 7H), 3.63 (s, 4H), 3.53 (t, J = 5.6 Hz, 3H), 3.23 (s,2H), 3.09 (s, 2H), 2.99-2.86 (m, 3H), 2.85-2.71 (m, 5H), 2.62 (d, J =6.1 Hz, 2H), 2.54-2.41 (m, 1H), 2.22-2.13 (m, 1H), 1.89 (d, J = 12.5 Hz,2H), 1.79- 1.71 (m, 2H), 1.66 (s, 1H), 1.44 (q, J = 11.2 Hz, 2H),1.09-0.87 (m, 2H), 0.80 (s, 2H). D311 885.45 ¹H NMR (400 MHz, DMSO-d6) δ10.96 (s, 1H), 8.20 (s, 1H, FA), 7.61 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H),7.13 (t, J = 5.8 Hz, 1H), 7.08-6.99 (m, 2H), 6.55 (s, 2H), 6.17-5.76 (m,1H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.39- 4.11 (m, 5H), 3.87 (d, J =12.3 Hz, 2H), 3.76 (s, 8H), 3.49 (s, 4H), 3.47- 3.33 (m, 6H), 2.98-2.76(m, 4H), 2.73-2.69 (m, 2H), 2.66-2.54 (m, 3H), 2.57-2.52 (m, 1H),2.41-2.32 (m, 1H), 2.00-1.92 (m, 1H), 1.76 (d, J = 12.5 Hz, 2H),1.63-1.39 (m, 3H), 1.30-1.17 (m, 2H), 0.68-0.63 (m, 2H), 0.48 (s, 2H).D312 885.45 ¹H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.21 (s, 2H,TFA), 7.62 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 8.6, 2.4 Hz,1H), 7.18-7.09 (m, 2H), 6.55 (s, 2H), 6.17-5.79 (m, 1H), 5.10 (dd, J =13.3, 5.1 Hz, 1H), 4.45-4.13 (m, 5H), 3.86-3.66 (m, 10H), 3.55-3.48 (m,5H), 3.48- 3.41 (m, 4H), 3.40-3.36 (m, 1H), 2.98-2.85 (m, 1H), 2.76-2.66(m, 6H), 2.65-2.55 (m, 3H), 2.45-2.34 (m, 1H), 2.03-1.96 (m, 1H), 1.77(d, J = 12.3 Hz, 2H), 1.51-1.47 (m, 3H), 1.28 (d, J = 11.7 Hz, 2H),0.69- 0.65 (m, 2H), 0.51 (s, 2H). D313 887.65 ¹H NMR (400 MHz,Methanol-d4) δ 7.81 (s, 1H), 7.71 (s, 2H), 7.58 (s, 1H), 6.73 (s, 2H),5.90 (tt, J = 56.7, 4.2 Hz, 1H), 5.18 (dd, J = 13.3, 5.2 Hz, 1H),4.77-4.45 (m, 3H), 4.41 (s, 2H), 4.30-4.01 (m, 1H), 3.95 (s, 6H), 3.80(d, J = 12.1 Hz, 2H), 3.65 (s, 3H), 3.62-3.49 (m, 4H), 3.42 (s, 2H),3.16 (br s, 1H), 3.00-2.76 (m, 3H), 2.75-2.61 (m, 5H), 2.61-2.42 (m,2H), 2.26-2.16 (m, 1H), 2.08 (d, J = 13.6 Hz, 2H), 1.82 (s, 1H), 1.67(s, 10H). D314 835.5 ¹H NMR (400 MHz, Methanol-d4) δ 7.54 (s, 1H), 7.46(d, J = 8.4 Hz, 1H), 7.39-7.30 (m, 2H), 6.61 (s, 2H), 5.15 (dd, J =13.3, 5.2 Hz, 1H), 4.63 (s, 1H), 4.50-4.35 (m, 2H), 4.36 (s, 2H), 4.23(s, 1H), 4.02-3.85 (m, 7H), 3.81 (d, J = 12.3 Hz, 2H), 3.66-3.61 (m,4H), 3.56-3.51 (m, 3H), 3.34- 3.20 (m, 2H), 3.09 (s, 2H), 2.96-2.77 (m,4H), 2.80-2.76 (m, 4H), 2.61 (s, 2H), 2.58-2.45 (m, 1H), 2.24-2.15 (m,1H), 1.92 (d, J = 12.4 Hz, 2H), 1.77 (s, 2H), 1.61 (s, 1H), 1.50 (q, J =10.8 Hz, 2H), 1.10 (s, 1H), 0.94- 0.73 (m, 3H). D315 871.6 ¹H NMR (300MHz, DMSO-d6) δ 10.98 (s, 1H), 8.18 (s, 1H, FA), 7.64 (s, 1H), 7.41 (d,J = 8.8 Hz, 1H), 6.76-6.68 (m, 2H), 6.63-6.58 (m, 3H), 5.10 (dd, 1H),4.39-4.13 (m, 4H), 3.89 (d, J = 7.9 Hz, 2H), 3.79 (s, 6H), 3.69 (d, J =8.0 Hz, 2H), 3.60 (s, 2H), 3.50 (s, 3H), 3.41 (s, 2H), 3.40 (s, 2H),2.98-2.82 (m, 3H), 2.59 (d, J = 4.2 Hz, 5H), 2.44-2.34 (m, 4H), 2.18 (d,J = 7.2 Hz, 4H), 2.00 (s, 3H), 1.63 (d, J = 12.6 Hz, 2H), 1.50 (s, 1H),1.17-1.02 (m, 2H). D316 862.5 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H),7.63 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 8.5, 2.4 Hz, 1H),7.15 (dd, J = 9.2, 4.1 Hz, 2H), 6.64 (s, 2H), 5.99 (t, J = 4.2 Hz, 1H),5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.43- 4.10 (m, 5H), 3.78 (d, J = 27.4Hz, 9H), 3.61 (s, 1H), 3.11 (s, 6H), 2.92 (s, 2H), 2.98-2.85 (m, 4H),2.72 (d, J = 11.9 Hz, 2H), 2.62 (s, 3H), 2.55 (s, 3H), 2.46-2.30 (m,3H), 2.06-1.89 (m, 1H), 1.82-1.68 (m, 2H), 1.53 (d, J = 40.7 Hz, 3H),1.35-1.20 (m, 2H),. D317 862.35 ¹H NMR (400 MHz, DMSO-d6) δ 10.95 (s,1H), 8.16 (s, 1H, FA), 7.65 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.13 (t,J = 5.7 Hz, 1H), 7.04 (s, 2H), 6.59 (s, 2H), 6.15-5.81 (m, 1H),5.09-4.99 (m, 1H), 4.37-4.12 (m, 4H), 3.85 (d, J = 12.6 Hz, 2H), 3.78(s, 6H), 3.53 (s, 2H), 3.49-3.39 (m, 6H), 2.95- 2.74 (m, 1H), 2.71-2.63(m, 2H), 2.63-2.57 (m, 1H), 2.57-2.54 (m, 3H), 2.47-2.40 (m, 3H),2.40-2.37 (m, 1H), 2.37-2.28 (m, 4H), 2.03- 1.88 (m, 1H), 1.73 (d, J =13.8 Hz, 2H), 1.50(s, 1H), 1.42-1.31 (m, 2H), 1.27-1.12 (m, 2H),. D318840.55 ¹H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.22 (s, 1H, FA), 7.63(s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.12-6.99 (m, 2H), 6.65-6.58 (m, 1H),6.56 (s, 2H), 5.05 (dd, J = 13.2, 5.1 Hz, 1H), 4.38-4.12 (m, 4H),3.92-3.81 (m, 4H), 3.78 (s, 6H), 3.49-3.34 (m, 4H), 3.00-2.70 (m, 5H),2.65-2.54 (m, 4H), 2.41-2.15 (m, 5H), 2.14-1.91 (m, 3H), 1.80-1.67 (m,2H), 1.60- 1.45 (m, 1H), 1.43-1.30 (m, 2H), 1.28-1.17 (m, 2H), 1.16-1.06(m, 6H). D319 840.55 ¹H NMR (300 MHz, Methanol-d4) δ 7.80-7.53 (m, 4H),6.75 (s, 2H), 5.18 (dd, J = 13.3, 5.1 Hz, 1H), 4.62-4.42 (m, 4H), 4.36(s, 2H), 3.98 (s, 6H), 3.93-3.72 (m, 5H), 3.61-3.50 (m, 3H), 3.29-3.21(m, 3H), 3.02-2.81 (m, 4H), 2.78 (s, 4H), 2.69-2.60 (m, 2H), 2.57-2.44(m, 1H), 2.30-2.15 (m, 1H), 2.12-1.97 (m, 2H), 1.91-2.69 (m, 4H),1.66-1.51 (m, 7H). D320 887.45 ¹H NMR (400 MHz, Methanol-d4) δ 7.68 (d,J = 9.2 Hz, 1H), 7.58 (s, 1H), 7.20-7.17 (m, 2H), 6.73 (s, 2H), 5.90(tt, J = 56.6, 4.2 Hz, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (s,1H), 4.53-4.33 (m, 4H), 4.13 (s, 1H), 3.95 (s, 7H), 3.92 (s, 1H), 3.64(s, 3H), 3.60-3.54 (m, 3H), 3.53-3.49 (m, 1H), 3.47 (s, 2H), 3.15 (s,1H), 3.05-2.93 (m, 3H), 2.96-2.86 (m, 1H), 2.85-2.75 (m, 4H), 2.64 (t, J= 5.2 Hz, 3H), 2.48 (qd, J = 13.2, 4.7 Hz, 1H), 2.23-2.12 (m, 1H), 1.90(d, J = 12.6 Hz, 2H), 1.68 (s, 7H), 1.66- 1.59 (m, 2H), 1.51-1.37 (m,2H). D321 849.55 ¹H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.62 (s,1H), 7.54 (d, J = 8.3 Hz, 1H), 7.11 (s, 2H), 6.72 (s, 2H), 5.04 (dd, J =13.2, 5.1 Hz, 1H), 4.58 (s, 1H), 4.38-4.14 (m, 4H), 3.97 (s, 3H), 3.89(s, 7H), 3.62-3.57 (m, 4H), 3.51 (s, 3H), 3.41 (t, J = 5.6 Hz, 2H),3.34-3.15 (m, 4H), 2.97- 2.78 (m, 3H), 2.67-2.55 (m, 6H), 2.56-2.50 (m,2H), 2.45-2.29 (m, 1H), 2.22 (s, 1H), 2.03-1.81 (m, 3H), 1.82-1.68 (m,4H), 1.64-1.55 (m, 1H), 1.31 (q, J = 10.7 Hz, 2H). D322 899.5 ¹H NMR(300 MHz, Methanol-d4) δ 7.69 (d, J = 9.1 Hz, 1H), 7.59 (s, 1H), 7.20(d, J = 7.1 Hz, 2H), 6.74 (s, 2H), 6.16-5.65 (m, 1H), 5.12 (dd, J =13.2, 5.1 Hz, 1H), 4.58-4.26 (m, 6H), 4.06-3.86 (m, 9H), 3.76-3.65 (m,4H), 3.67-3.46 (m, 7H), 3.40 (s, 2H), 3.24 (s, 2H), 3.03 (t, J = 12.2Hz, 2H), 2.94-2.78 (m, 2H), 2.78-2.69 (m, 2H), 2.67-2.61 (m, 2H),2.57-2.34 (m, 2H), 2.22-2.02 (m, 3H), 1.94 (d, J = 12.5 Hz, 2H), 1.74(d, J = 33.3 Hz, 3H), 1.61-1.38 (m, 2H). D323 840.5 ¹H NMR (300 MHz,Methanol-d4) δ 8.49 (s, 2H, FA), 7.58 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H),7.37-7.30 (m, 2H), 6.73 (s, 2H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H),4.54-4.46 (m, 1H), 4.43-4.29 (m, 5H), 3.96 (s, 6H), 3.84- 3.68 (m, 4H),3.64 (s, 3H), 3.55 (t, J = 5.3 Hz, 2H), 3.37 (s, 1H), 2.96- 2.72 (m,6H), 2.64 (s, 3H), 2.58-2.44 (m, 3H), 2.24-2.12 (m, 1H), 1.95- 1.83 (m,2H), 1.62-1.42 (m, 9H), 1.42-1.22 (m, 2H). D324 840.5 ¹H NMR (400 MHz,Methanol-d4) δ 7.68 (d, J = 9.3 Hz, 1H), 7.58 (s, 1H), 7.20-7.17 (m,2H), 6.74 (s, 2H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 13.5Hz, 1H), 4.50-4.41 (m, 3H), 4.36 (s, 2H), 4.04-3.88 (m, 10H), 3.64 (s,4H), 3.55 (t, J = 5.6 Hz, 2H), 3.37 (s, 1H), 3.24-3.13 (m, 1H),3.08-2.84 (m, 6H), 2.83-2.75 (m, 1H), 2.68-2.59 (m, 2H), 2.52-2.41 (m,1H), 2.23-2.12 (m, 1H), 1.91 (d, J = 12.9 Hz, 2H), 1.77-1.67 (m, 3H),1.61 (d, J = 6.6 Hz, 6H), 1.52-1.40 (m, 2H). D325 837.4 ¹H NMR (400 MHz,Methanol-d4) δ 8.57 (s, 1H, FA), 7.63 (d, J = 8.6 Hz, 1H), 7.57 (s, 1H),7.11-7.05 (m, 2H), 6.72 (s, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H),4.94-4.89 (m, 1H), 4.46 (s, 1H), 4.46-4.37 (m, 2H), 4.36 (s, 3H),3.97-3.91 (m, 8H), 3.73-3.66 (m, 1H), 3.64 (s, 3H), 3.55 (t, J = 5.6 Hz,2H), 3.00-2.89 (m, 1H), 2.89-2.80 (m, 3H), 2.78 (s, 5H), 2.63 (t, J =5.6 Hz, 3H), 2.60-2.39 (m, 4H), 2.21-2.10 (m, 1H), 1.92-1.83 (m, 2H),1.65 (s, 1H), 1.58-1.48 (m, 8H), 1.44-1.29 (m, 3H). D326 837.45 ¹H NMR(400 MHz, Methanol-d4) δ 8.57 (s, 1H, FA), 7.58 (s, 1H), 7.45 (d, J =8.4 Hz, 1H), 7.39-7.26 (m, 2H), 6.73 (s, 2H), 5.15 (dd, J = 13.3, 5.1Hz, 1H), 4.49-4.34 (m, 3H), 4.36 (s, 3H), 3.96 (s, 6H), 3.77 (d, J =12.3 Hz, 2H), 3.74-3.66 (m, 1H), 3.64 (s, 3H), 3.55 (t, J = 5.6 Hz, 2H),3.01- 2.86 (m, 2H), 2.86-2.76 (m, 6H), 2.75 (s, 1H), 2.64 (t, J = 5.7Hz, 3H), 2.60-2.42 (m, 4H), 2.26-2.13 (m, 1H), 1.89 (s, 2H), 1.52 (d, J= 6.6 Hz, 9H), 1.48-1.35 (m, 3H). D327 807.55 ¹H NMR (300 MHz, DMSO-d6)δ 10.99 (s, 1H), 8.19 (s, 1H), 7.61 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H),7.25 (d, J = 8.1 Hz, 1H), 7.15 (s, 1H), 6.76 (s, 2H), 6.60 (d, J = 4.2Hz, 1H), 5.10 (dd, J = 13.2, 4.8 Hz, 1H), 4.33 (d, J = 17.1 Hz, 1H),4.25-4.14 (m, 3H), 3.90-3.70 (m, 7H), 3.49 (s, 3H), 3.39 (s, 4H),2.99-2.84 (m, 2H), 2.78-2.65 (m, 4H), 2.65-2.55 (m, 4H), 2.44- 2.30 (m,10H), 2.04-1.93 (m, 1H), 1.75 (d, J = 11.7 Hz, 2H), 1.55-1.35 (m, 3H),1.35-1.12 (m, 5H). D328 876.3 ¹H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H),7.65 (t, J = 4.3 Hz, 2H), 7.32-7.09 (m, 3H), 6.58 (s, 2H), 5.99 (tt, J =56.7, 4.3 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.26 (s, 2H), 4.03(d, J = 12.7 Hz, 2H), 3.77 (s, 6H), 3.51 (s, 2H), 3.46 (m, 2H), 3.44 (m,2H), 3.43 (m, 2H), 2.91 (q, J = 14.2, 13.3 Hz, 4H), 2.61 (d, J = 3.6 Hz,1H), 2.35 (d, J = 30.3 Hz, 10H), 2.01 (d, J = 11.0 Hz, 1H), 1.74 (d, J =12.6 Hz, 2H), 1.57 (s, 1H), 1.35 (d, J = 7.3 Hz, 2H), 1.19 (dd, J =20.1, 9.1 Hz, 2H). D329 853.4 ¹H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H),7.63 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.10-7.04 (m, 2H), 6.70 (s, 2H),6.62 (s, 1H), 5.05 (dd, J = 13.3, 5.1 Hz, 1H), 4.32 (d, J = 16.9 Hz,1H), 4.25-4.15 (m, 4H), 3.85- 3.83 (m, 2H), 3.81-3.73 (m, 8H), 3.72-3.58(m, 4H), 3.51 (s, 4H), 3.42 (s, 6H), 3.27-2.99 (m, 5H), 2.98-2.84 (m,4H), 2.64-2.56 (m, 4H), 2.45- 2.28 (m, 1H), 2.02-1.89 (m, 1H), 1.75 (d,J = 12.4 Hz, 2H), 1.65-1.48 (m, 3H), 1.33-1.17 (m, 2H). D330 845.4 ¹HNMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.24 (s, 2H, FA), 7.64 (s, 1H),7.52 (d, J = 8.4 Hz, 1H), 7.17-7.06 (m, 2H), 6.59 (s, 3H), 5.05 (dd, J =13.2, 5.0 Hz, 1H), 4.37-4.29 (m, 1H), 4.25-4.19 (m, 3H), 4.11-4.07 (m,1H), 3.90-3.86 (m, 2H), 3.78 (s, 6H), 3.54-3.47 (m, 5H), 3.40 (t, J =5.6 Hz, 3H), 3.24 (dd, J = 30.5, 13.2 Hz, 2H), 3.05-2.84 (m, 2H), 2.64-2.57 (m, 4H), 2.47-2.26 (m, 10H), 2.15-2.06 (m, 1H), 2.01-1.81 (m, 3H),1.53-1.40 (m, 1H), 1.37-1.18 (m, 1H). D331 655.4 1H NMR (400 MHz,DMSO-d6) δ 10.94 (s, 1H), 7.60 (s, 1H), 7.51 (d, J = 8.3 Hz, 1H),6.64-6.49 (m, 5H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.36- 4.28 (m, 4H),4.24-4.15 (m, 3H), 4.03-3.97 (m, 2H), 3.73 (s, 6H), 3.48 (s, 3H), 3.38(t, J = 5.5 Hz, 2H), 2.97-2.83 (m, 1H), 2.63-2.53 (m, 6H), 2.42-2.27 (m,1H), 1.99-1.92 (m, 1H). D332 849.5 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s,1H), 7.62 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.5, 2.3 Hz,1H), 7.32 (d, J = 2.3 Hz, 1H), 6.73 (s, 2H), 5.09 (dd, J = 13.3, 5.1 Hz,1H), 4.65-4.43 (m, 1H), 4.44-4.15 (m, 4H), 3.89 (s, 6H), 3.81-3.76 (m,4H), 3.57-3.31 (m, 4H), 3.41- 3.30 (m, 3H), 3.24-3.06 (m, 5H), 2.94-2.84(m, 4H), 2.75-2.63 (m, 5H), 2.61-2.57 (m, 3H), 2.56-2.52 (m, 1H),2.14-2.05 (m, 1H), 2.04- 1.96 (m, 1H), 1.96-1.79 (m, 4H), 1.74-1.69 (m,2H), 1.60-1.56 (m, 1H), 1.46-1.36 (m, 2H). D333 899.5 ¹H NMR (300 MHz,Methanol-d4) δ 7.72-7.56 (m, 4H), 6.74 (s, 2H), 6.16- 5.60 (m, 1H),5.24-5.08 (m, 1H), 4.62-4.22 (m, 6H), 3.97 (s, 6H), 3.80 (d, J = 12.0Hz, 2H), 3.70-3.46 (m, 8H), 3.44-3.33 (m, 4H), 3.29- 3.16 (m, 4H), 3.06(s, 2H), 2.96-2.68 (m, 2H), 2.68-2.59 (m, 4H), 2.57- 2.46 (m, 1H), 2.41(s, 1H), 2.12 (dt, J = 45.4, 6.8 Hz, 5H), 1.83-1.47 (m, 5H). D334 875.4¹H NMR (300 MHz, Methanol-d4) δ 7.59 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H),7.04-6.67 (m, 4H), 5.14 (dd, J = 13.1, 5.1 Hz, 1H), 4.66-4.48 (m, 2H),4.45-4.31 (m, 4H), 4.31-4.12 (m, 4H), 3.97 (s, 6H), 3.93-3.89 (m, 2H),3.87-3.57 (m, 9H), 3.55 (t, J = 5.6 Hz, 3H), 2.98-2.80 (m, 3H), 2.78 (s,3H), 2.76-2.66 (m, 2H), 2.66-2.60 (m, 2H), 2.57-2.43 (m, 1H), 2.26-2.13(m, 1H), 2.11-1.98 (m, 1H), 1.93-1.70 (m, 3H). D335 868.55 ¹H NMR (300MHz, DMSO-d6) δ 10.98 (s, 1H), 8.14 (s, 0.4H, FA), 7.65 (s, 1H), 7.39(d, J = 8.3 Hz, 1H), 7.33-7.25 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H),6.73-6.64 (m, 2H), 6.57 (s, 2H), 5.39 (d, J = 8.0 Hz, 1H), 5.08 (dd, J =13.3, 5.1 Hz, 1H), 4.61 (s, 2H), 4.36-4.16 (m, 2H), 3.80 (s, 6H), 3.72-3.57 (m, 6H), 3.48 (s, 3H), 3.14-2.81 (m, 5H), 2.70-2.56 (m, 5H), 2.49-2.30 (m, 4H), 2.27-2.05 (m, 3H), 2.04-1.58 (m, 6H), 1.51-1.32 (m, 1H).D336 885.4 ¹H NMR (400 MHz, MeOD) δ 8.47 (s, 2FA, 2H), 7.59 (s, 1H),7.40 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.78 (dd, J = 8.2,2.2 Hz, 1H), 6.73 (s, 2H), 6.07-5.71 (m, 1H), 5.14 (dd, J = 13.3, 5.1Hz, 1H), 4.47-4.32 (m, 6H), 3.95 (s, 6H), 3.67 (d, J = 18.9 Hz, 7H),3.61-3.48 (m, 6H), 3.15- 3.10 (m, 2H), 2.98-2.57 (m, 8H), 2.56-2.42 (m,3H), 2.21-2.14 (m, 1H), 2.09-2.0 (m, 3H), 1.99-1.93 (m, 5H), 1.58-1.53(m, 2H). D337 837.5 ¹H NMR (300 MHz, DMSO-d6) δ 7.65 (d, J = 8.5 Hz,1H), 7.29-7.16 (m, 2H), 6.50 (s, 2H), 4.99 (dd, J = 12.7, 5.5 Hz, 1H),4.19 (d, J = 16.7 Hz, 4H), 3.96 (s, 3H), 3.77 (s, 6H), 3.50 (s, 4H),3.34 (s, 8H), 3.10 (s, 2H), 2.94 (t, J = 12.3 Hz, 2H), 2.84-2.72 (m,1H), 2.63 (d, J = 3.4 Hz, 1H), 2.55 (s, 3H), 2.4-2.5 (m, 1H), 2.18 (s,2H), 2.10 (s, 3H), 2.06-1.96 (m, 1H), 1.73 (d, J = 12.4 Hz, 2H), 1.57(s, 3H), 1.17 (d, J = 12.4 Hz, 2H). D338 900.45 ¹H NMR (400 MHz,DMSO-d6) δ 11.13 (s, 1H), 8.03 (t, 1H), 7.86-7.71 (m, 1H), 7.57 (s, 1H),7.35-7.21 (m, 2H), 6.73-6.59 (m, 3H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H),4.98 (t, J = 6.8 Hz, 1H), 4.25 (s, 2H), 3.79 (s, 6H), 3.59 (s, 3H), 3.42(t, J = 5.5 Hz, 3H), 2.99-2.81 (m, 3H), 2.66-2.57 (m, 5H), 2.46-2.37 (m,2H), 2.37-1.98 (m, 9H), 1.80 (dd, J = 12.3, 6.3 Hz, 2H), 1.70-1.59 (m,4H), 1.56 (t, J = 5.1 Hz, 2H), 1.48 (s, 1H), 1.17-0.98 (m, 2H). D339871.5 ¹H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H, FA), 7.65-7.54 (m,2H), 6.70 (s, 2H), 6.61-6.51 (m, 2H), 5.09 (dd, J = 13.2, 5.1 Hz, 1H),4.61 (s, 2H), 4.47-4.27 (m, 6H), 4.05 (d, J = 7.9 Hz, 2H), 3.93 (s, 6H),3.74 (d, J = 8.0 Hz, 2H), 3.63 (s, 3H), 3.53 (t, J = 5.6 Hz, 4H),3.17-3.01 (m, 2H), 2.95-2.85 (m, 1H), 2.82-2.73 (m, 4H), 2.72-2.58 (m,3H), 2.57-2.39 (m, 3H), 2.37-2.27 (m, 2H), 2.18-2.07 (m, 3H), 2.05-1.97(m, 2H), 1.96-1.83 (m, 1H), 1.51-1.40(m, 1H). D340 853.4 ¹H NMR (400MHz, DMSO-d6) δ 10.99 (s, 1H), 7.63 (s, 1H), 7.44 (d, J = 8.5 Hz, 1H),7.33-7.26 (m, 1H), 7.20 (s, 1H), 6.70 (s, 2H), 6.62 (s, 1H), 5.10 (dd, J= 13.3, 5.1 Hz, 1H), 4.34 (d, J = 16.8 Hz, 1H), 4.25-4.17 (m, 4H),3.81-3.77 (m, 8H), 3.76-3.72 (m, 6H), 3.51 (s, 3H), 3.40 (s, 6H),3.24-3.00 (m, 4H), 2.98-2.85 (m, 3H), 2.76 (t, J = 11.9 Hz, 3H), 2.65-2.52 (m, 4H), 2.43-2.34 (m, 1H), 2.04-1.94 (m, 1 H), 1.78 (d, J = 12.3Hz, 2H), 1.66-1.45 (m, 3H), 1.39-1.23 (m, 2H). D341 812.45 ¹H NMR (300MHz, MeOD) δ 8.52 (s, FA, 1H), 7.57 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H),7.38-7.27 (m, 2H), 6.68 (s, 2H), 5.15 (dd, J = 13.2, 5.1 Hz, 1H),4.51-4.33 (m, 4H), 4.11 (s, 2H), 3.91 (s, 6H), 3.77 (d, J = 12.2 Hz,2H), 3.64 (s, 3H), 3.54 (t, J = 5.7, 5.7 Hz, 2H), 3.15-3.03 (m, 4H),3.00- 2.85 (m, 4H), 2.85-2.68 (m, 6H), 2.66-2.61 (m, 2H), 2.59-2.42 (m,1H), 2.23-2.13 (m, 1H), 1.87 (d, J = 12.3 Hz, 2H), 1.64-1.55 (m, 3H),1.51-1.38 (m, 2H). D342 850.35 ¹H NMR (400 MHz, Methanol-d4) δ 8.53 (s,2H, FA), 8.10-7.81 (m,, 3H), 7.59 (s, 1H), 6.73 (s, 2H), 5.16 (dd, J =12.6, 5.4 Hz, 1H), 4.37 (d, J = 3.4 Hz, 4H), 4.26-4.09 (m, 1 H), 3.95(s, 6H), 3.80-3.65 (m, 4H), 3.59-3.36 (m, 6H), 3.11 (s, 3H), 2.90 (ddd,J = 17.6, 14.3, 5.1 Hz, 1H), 2.83-2.69 (m, 5H), 2.64 (t, J = 5.5 Hz,2H), 2.30 (t, J = 13.5 Hz, 1H), 2.21-2.09 (m, 2H), 2.04 (d, J = 12.7 Hz,3H), 1.96 (s, 1H), 1.78 (s, 3H), 1.65 (s, 2H), 1.58- 1.49 (m, 3H), 1.45(d, J = 6.2 Hz, 3H). D343 932.4 ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s,1H), 8.19 (s, FA, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.62 (s, 1H), 7.32-7.24(m, 2H), 6.64-6.55 (m, 3H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 5.01-4.94(m, 1H), 4.21 (s, 2H), 3.86-3.71 (m, 8H), 3.54-3.47 (m, 5H), 3.05-2.90(m, 2H), 2.90-2.76 (m, 5H), 2.73-2.68 (m, 1H), 2.64-2.55 (m, 5H),2.45-2.40 (m, 4H), 2.07-1.96 (m, 3H), 1.92-1.75 (m, 3H), 1.64-1.45 (m,6H), 1.32-1.11 (m, 2H). D344 859.45 ¹H NMR (400 MHz, Methanol-d4) δ 7.69(d, J = 2.1 Hz, 1H), 7.66-7.57 (m, 3H), 6.74 (s, 2H), 6.13-5.65 (m, 1H),5.22-5.13 (m, 1H), 4.62- 4.37 (m, 6H), 3.95 (s, 6H), 3.88-3.74 (m, 3H),3.65 (s, 3H), 3.60-3.55 (m, 7H), 3.53-3.49 (m, 1H), 3.44 (s, 3H),3.27-3.20 (m, 2H), 3.19-3.09 (m, 2H), 2.99-2.85 (m, 1H), 2.81-2.76 (m,1H), 2.66 (t, J = 5.6 Hz, 2H), 2.59-2.44 (m, 1H), 2.25-2.15(m, 1H), 2.03(d, J = 13.2 Hz, 2H), 1.77- 1.73 (m, 3H), 1.68-1.58 (m, 2H). D345 918.45¹H NMR (400 MHz, Methanol-d4) δ 7.58 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H),7.20 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 8.3, 2.4 Hz, 1H), 6.74 (d, J =4.1 Hz, 2H), 5.16 (dd, J = 13.3, 5.1 Hz, 1H), 4.79 (t, J = 6.7 Hz, 1H),4.50-4.42 (m, 2H), 4.36 (s, 4H), 3.96 (s, 6H), 3.69-3.59 (m, 5H), 3.55(t, J = 5.6 Hz, 2H), 3.38-3.35 (m, 1H), 3.20-3.08 (m, 2H), 3.00-2.84 (m,4H), 2.84- 2.81 (m, 1H), 2.78 (s, 3H), 2.68-2.58 (m, 3H), 2.57-2.45 (m,4H), 2.37 (d, J = 14.8 Hz, 1H), 2.24-2.01 (m, 4H), 1.96-1.87 (m, 2H),1.74-1.52 (m, 6H). D346 845.4 ¹H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H),8.36 (s, 3H, FA), 7.64 (s, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.30 (d, J =8.4 Hz, 1H), 7.20 (s, 1H), 6.58 (s, 3H), 5.10 (dd, J = 13.4, 4.9 Hz,1H), 4.40-4.31 (m, 1H), 4.25-4.16 (m, 3H), 4.02-3.89 (m, 3H), 3.78 (s,6H), 3.52-3.49 (m, 5H), 3.42- 3.37 (m, 3H), 3.23-3.14 (m, 1H), 3.14-3.05(m, 1H), 2.97-2.84 (m, 2H), 2.62-2.56 (m, 4H), 2.44-2.28 (m, 10H),2.05-1.94 (m, 2H), 1.92- 1.72 (m, 2H), 1.57-1.44 (m, 1H), 1.36-1.22 (m,1H). D347 882.4 ¹H NMR (300 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.21 (d, J =73.7 Hz, TFA 2H), 7.86 (d, J = 8.3 Hz, 1H), 7.77 (s, 1H), 7.34 (d, J =2.3 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 6.77 (s, 2H), 6.66 (d, J = 4.5Hz, 1H), 6.13 (s, 1H), 5.96 (s, 1H), 5.13 (dd, J = 12.9, 5.3 Hz, 1H),5.05-4.97 (m, 1H), 4.23 (d, J = 14.7 Hz, 4H), 3.88 (s, 6H), 3.18 (s,2H), 3.07-2.78 (m, 7H), 2.60 (d, J = 4.1 Hz, 8H), 2.18-1.69 (m, 11H),1.63-1.39 (m, 2H). D348 737.4 1H), 7.61-7.55 (m, 2H), 7.51 (dd, J = 8.4,2.2 Hz, 1H), 6.80 (s, 2H), 5.17 (dd, J = 13.3, 5.2 Hz, 1H), 4.54-4.43(m, 2H), 4.40 (s, 2H), 3.97 (s, 6H), 3.79 (d, J = 12.1 Hz, 2H), 3.67 (s,3H), 3.48-3.42 (m, 5H), 3.32-3.24 (m, 3H), 3.15-3.01 (m, 6H), 2.92-2.84(m, 3H), 2.84-2.74 (m, 1H), 2.60- 2.42 (m, 1H), 2.24-2.07 (m, 3H),2.03-1.94 (m, 2H), 1.75-1.67 (m, 3H), 1.60-1.50 (m, 2H). D349 796.25 ¹HNMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.30-9.27 (m, 2H, TFA), 7.63(d, J = 7.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.80-6.67 (m, 4H), 5.07(dd, J = 13.2, 5.1 Hz, 1H), 4.43-4.26 (m, 6H), 4.24-4.18 (m, 2H), 4.10-3.94 (m, 3H), 3.89 (d, J = 3.2 Hz, 6H), 3.76-3.70 (m, 2H), 3.69-3.59 (m,5H), 3.51 (s, 3H), 3.27-3.08 (m, 2H), 3.05-2.84 (m, 3H), 2.70-2.56 (m,4H), 2.45-2.36 (m, 1H), 2.17-2.06 (m, 2H), 2.03-1.88 (m, 3H). D350736.25 ¹H NMR (300 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.41 (d, J = 8.8 Hz,1H), 6.79-6.66 (m, 4H), 5.04 (dd, J = 13.2, 5.1 Hz, 1H), 4.34 (dd, J =17.0, 5.4 Hz, 3H), 4.25-4.14 (m, 3H), 4.04-3.92 (m, 2H), 3.89 (s, 6H),3.71 (s, 2H), 3.57-3.49 (m, 3H), 3.42 (s, 5H), 3.36 (s, 3H), 3.26-3.10(m, 1H), 3.05-2.92 (m, 3H), 2.82 (q, J = 11.6, 9.6 Hz, 2H), 2.60 (d, J =16.7 Hz, 1H), 2.36 (dt, J = 13.5, 6.6 Hz, 1H), 2.11 (d, J = 13.7 Hz,2H), 1.93 (td, J = 17.8, 16.9, 9.8 Hz, 3H). D351 695.25 ¹H NMR (400 MHz,Methanol-d4) δ 8.56 (s, 1H, FA), 7.66 (d, J = 8.2 Hz, 1H), 6.88 (s, 1H),6.86 (d, J = 2.1 Hz, 1H), 6.69 (dd, J = 8.4, 2.1 Hz, 1H), 6.65 (s, 2H),5.08 (dd, J = 12.5, 5.4 Hz, 1H), 4.10-3.98 (m, 2H), 3.98- 3.88 (m, 6H),3.89-3.80 (m, 4H), 3.62 (s, 3H), 3.40 (t, J = 5.6 Hz, 2H), 3.05-2.81 (m,4H), 2.81-2.68 (m, 3H), 2.56 (t, J = 6.2 Hz, 2H), 2.19- 1.97 (m, 5H),1.85 (q, J = 5.9 Hz, 2H). D352 750.3 ¹H NMR (400 MHz, DMSO-d6) δ 10.97(s, 1H), 8.21 (s, 2H, FA), 7.47 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 6.68(d, J = 10.2 Hz, 2H), 6.63 (s, 2H), 5.08 (dd, J = 13.3, 5.1 Hz, 1H),4.38-4.14 (m, 2H), 3.81 (s, 7H), 3.57 (s, 6H), 3.40 (d, J = 16.8 Hz,4H), 3.29 (dd, J = 6.9, 4.7 Hz, 1H), 3.15 (s, 3H), 2.98- 2.84 (m, 1H),2.77-2.68 (m, 2H), 2.59 (d, J = 16.1 Hz, 2H), 2.42 (d, J = 6.8 Hz, 2H),2.39 (s, 3H), 2.28 (s, 4H), 1.98 (d, J = 12.0 Hz, 1H), 1.72 (t, J = 5.3Hz, 4H). D353 763.6 ¹H NMR (300 MHz, MeOD) δ 7.71 (s, 1H), 7.42 (d, J =8.2 Hz, 1H), 6.88 (d, J = 2.2 Hz, 1H), 6.80 (d, J = 3.3 Hz, 3H), 5.14(dd, J = 13.2, 5.1 Hz, 1H), 4.53-4.31 (m, 4H), 3.98 (d, J = 3.5 Hz, 6H),3.78 (d, J = 23.5 Hz, 4H), 3.70-3.58 (m, 7H), 3.31-3.25 (m, 1H),3.24-2.96 (m, 7H), 2.96- 2.74 (m, 4H), 2.59-2.42 (m, 1H), 2.34-2.00 (m,10H), 1.78-1.55 (m, 2H). D354 807.45 ¹H NMR (400 MHz, DMSO-d6) δ 10.98(s, 1H), 8.87 (s, 1H), 8.23 (s, 2H, FA), 7.64-7.47 (m, 2H), 7.07-6.92(m, 2H), 6.59 (s, 2H), 5.07 (dd, J = 13.4, 5.1 Hz, 1H), 4.86-4.78 (m,1H), 4.38 (d, J = 17.2 Hz, 1H), 4.25 (d, J = 17.3 Hz, 1H), 3.79 (s, 6H),3.55 (s, 3H), 3.53 (s, 2H), 2.93-2.77 (m, 5H), 2.64-2.59 (m, 1H),2.45-2.36 (m, 5H), 2.29-2.17 (m, 4H), 2.08- 1.99 (m, 5H), 1.80-1.75 (m,2H), 1.61-1.51 (m, 6H), 1.45-1.41 (m, 1H), 1.07-0.99 (m, 2H). D355868.55 ¹H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.14 (s, 0.4H, FA),7.65 (s, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.33-7.25 (m, 1H), 7.20 (d, J =8.0 Hz, 1H), 6.73-6.64 (m, 2H), 6.57 (s, 2H), 5.39 (d, J = 8.0 Hz, 1H),5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (s, 2H), 4.36-4.16 (m, 2H), 3.80(s, 6H), 3.72- 3.57 (m, 6H), 3.48 (s, 3H), 3.14-2.81 (m, 5H), 2.70-2.56(m, 5H), 2.49- 2.30 (m, 4H), 2.27-2.05 (m, 3H), 2.04-1.58 (m, 6H),1.51-1.32 (m, 1H). D356 666.4 ¹H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H),8.20 (s, 1H, FA), 7.76 (s, 1H), 7.37 (d, J = 8.1 Hz, 1H), 6.73-6.62 (m,4H), 5.08 (dd, J = 13.2, 5.0 Hz, 1H), 4.38-4.12 (m, 2H), 3.82 (s, 6H),3.56 (s, 3H), 3.53-3.47 (m, 6H), 3.02-2.82 (m, 3H), 2.72 (t, J = 7.5 Hz,2H), 2.65-2.56 (m, 1H), 2.45- 2.27 (m, 5H), 2.05-1.94 (m, 3H), 1.81-1.63(m, 4H). D357 668.25 ¹H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H, FA), 7.98(s, 1H), 7.37 (d, J = 8.1 Hz, 1H), 6.73-6.62 (m, 4H), 5.20 (s, 2H), 5.06(dd, J = 13.2, 5.1 Hz, 1H), 4.93 (s, 2H), 4.38-4.12 (m, 2H), 3.82 (s,6H), 3.60-3.51 (m, 9H), 2.98-2.80 (m, 1H), 2.65-2.53 (m, 3H), 2.42-2.26(m, 3H), 2.03-1.93 (m, 1H), 1.79-1.69 (m, 4H). D358 682.25 ¹H NMR (300MHz, DMSO-d6) δ 8.22 (s, 1H, FA), 7.98 (s, 1H), 7.62 (d, J = 8.2 Hz,1H), 6.76 (d, J = 2.0 Hz, 1H), 6.64 (s, 3H), 5.20 (s, 2H), 5.04 (dd, J =12.8, 5.3 Hz, 1H), 4.93 (s, 2H), 3.81 (s, 6H), 3.72 (s, 4H), 3.56 (s,3H), 3.53 (s, 2H), 2.90-2.78 (m, 1H), 2.64-2.52 (m, 2H), 2.47-2.35 (m,4H), 2.05-1.95 (m, 1H), 1.76-1.70 (m, 4H). D359 668.25 ¹H NMR (300 MHz,DMSO-d6) δ 8.22 (s, 1H, FA), 7.98 (s, 1H), 7.48 (d, J = 8.2 Hz, 1H),6.65 (s, 2H), 6.54-6.43 (m, 2H), 5.20 (s, 2H), 5.01 (dd, J = 13.3, 5.0Hz, 1H), 4.92 (s, 2H), 4.36-4.02 (m, 2H), 3.82 (s, 6H), 3.61 (s, 9H),2.88 (t, J = 14.3 Hz, 1H), 2.68-2.50 (m, 5H), 2.40-2.29 (m, 1H),2.00-1.91 (m, 1H), 1.79-1.73 (m, 4H). D360 681.4 ¹H NMR (400 MHz,DMSO-d6) δ 10.95 (s, 1H), 8.14 (s, 0.2H, FA), 7.50 (d, J = 8.2 Hz, 1H),6.90 (s, 1H), 6.64 (s, 2H), 6.57-6.45 (m, 2H), 5.49 (s, 1H), 5.04 (dd, J= 13.3, 5.1 Hz, 1H), 4.35-4.16 (m, 2H), 4.10-3.78 (m, 8H), 3.69 (s, 4H),3.48 (s, 3H), 3.26 (s, 3H), 3.01-2.79 (m, 3H), 2.65- 2.55 (m, 2H),2.48-2.43 (m, 2H), 2.41-2.35 (m, 1H), 2.05-1.77 (m, 5H), 1.69 (s, 2H),D361 681.35 ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.15 (s, 0.2H,FA), 7.39 (d, J = 8.1 Hz, 1H), 6.90 (s, 1H), 6.69 (d, J = 7.6 Hz, 2H),6.66-6.52 (m, 2H), 5.47 (d, J = 2.8 Hz, 1H), 5.08 (dd, J = 13.3, 5.1 Hz,1H), 4.35-4.16 (m, 2H), 3.91-3.74 (m, 8H), 3.62 (s, 4H), 3.48 (s, 3H),3.26 (s, 4H), 2.96- 2.87 (m, 1H), 2.85-2.70 (m, 2H), 2.64-2.55 (m, 1H),2.50-2.45 (m, 2H), 2.43-2.33 (m, 1H), 2.03-1.94 (m, 1H), 1.84 (s, 4H),1.70 (s, 2H). D362 627.2 ¹H NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H),7.88-7.80 (m, 1H), 7.76 (s, 1H), 7.27 (d, J = 7.4 Hz, 2H), 6.67 (s, 2H),5.12 (dd, J = 12.8, 5.3 Hz, 1H), 4.97 (s, 1H), 3.81 (s, 9H), 3.51 (s,3H), 3.28-3.12 (m, 3H), 3.01- 2.80 (m, 3H), 2.70 (d, J = 7.6 Hz, 2H),2.60 (d, J = 13.7 Hz, 2H), 2.00 (q, J = 7.5 Hz, 3H). D363 680.2 ¹H NMR(300 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.18 (s, 1H, FA), 7.76 (s, 1H), 7.63(d, J = 8.3 Hz, 1H), 6.78 (d, J = 2.1 Hz, 1H), 6.69-6.60 (m, 3H), 5.05(dd, J = 12.8, 5.3 Hz, 1H), 3.81 (s, 6H), 3.73 (s, 3H), 3.51 (s, 5H),2.96 (t, J = 7.5 Hz, 3H), 2.90-2.80 (m, 1H), 2.78-2.55 (m, 4H), 2.41 (s,4H), 1.99 (t, J = 7.7 Hz, 3H), 1.72 (s, 4H). D364 626.25 ¹H NMR (300MHz, DMSO-d6) δ 10.98 (s, 1H), 7.77 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H),7.29-7.20 (m, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.67 (s, 2H), 5.09 (dd, J =13.2, 5.1 Hz, 1H), 4.39-4.13 (m, 2H), 3.83 (s, 6H), 3.60 (s, 2H), 3.51(s, 3H), 3.16 (s, 4H), 3.01-2.83 (m, 3H), 2.70 (d, J = 7.4 Hz, 2H), 2.58(s, 5H), 2.41-2.30 (m, 1H), 1.98 (d, J = 8.4 Hz, 3H). D365 621.35 ¹H NMR(400 MHz, Methanol-d4) δ 8.53 (s, 1H, FA), 7.83 (s, 1H), 7.76- 7.66 (m,2H), 7.60 (d, J = 7.9 Hz, 1H), 6.79 (s, 2H), 5.17 (dd, J = 13.3, 5.2 Hz,1H), 4.60-4.45 (m, 2H), 4.41-4.27 (m, 4H), 4.10 (q, J = 7.6 Hz, 2H),3.97 (s, 6H), 3.85 (q, J = 8.2 Hz, 1H), 3.66 (s, 3H), 3.06-2.75 (m, 6H),2.51 (qd, J = 13.2, 4.7 Hz, 1H), 2.24-2.18 (m, 1H), 2.15-2.02 (m, 2H).D366 640.3 ¹H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.76 (s, 1H), 7.67(d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 7.23 (d, J = 8.6 Hz, 1H), 6.68 (s,2H), 5.07 (dd, J = 13.1, 5.3 Hz, 1H), 3.83 (s, 6H), 3.67-3.57 (m, 2H),3.51 (s, 3H), 3.40 (s, 5H), 2.96 (t, J = 7.3 Hz, 2H), 2.86 (d, J = 14.5Hz, 1H), 2.70 (d, J = 7.5 Hz, 2H), 2.63-2.55 (m, 5H), 1.98 (q, J = 8.7,7.2 Hz, 3H). D367 623.15 ¹H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.14(s, 0.4H, FA), 8.01 (s, 1H), 7.74-7.58 (m, 3H), 6.69 (s, 2H), 5.20 (t, J= 3.5 Hz, 2H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.92 (t, J = 3.4 Hz,2H), 4.57-4.30 (m, 2H), 4.02- 3.89 (m, 4H), 3.86 (s, 6H), 3.67-3.53 (m,6H), 3.01-2.83 (m, 1H), 2.67- 2.55 (m, 1H), 2.49-2.30 (m, 1H), 2.08-1.96(m, 1H). D368 623.2 ¹H NMR (300 MHz, DMSO-d6 with a drop of D2O) δ 8.17(s, 0.4H, FA), 7.96 (s, 1H), 7.70 (dd, J = 7.9, 0.7 Hz, 1H), 7.64 (t, J= 1.1 Hz, 1H), 7.52 (dd, J = 7.9, 1.4 Hz, 1H), 6.64 (s, 2H), 5.17 (d, J= 3.5 Hz, 2H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.92 (d, J = 3.3 Hz,2H), 4.50-4.19 (m, 2H), 3.82 (s, 6H), 3.71-3.61 (m, 4H), 3.55 (s, 3H),3.40 (q, J = 7.2 Hz, 1H), 3.29 (t, J = 7.0 Hz, 2H), 2.98-2.80 (m, 1H),2.67-2.55 (m, 1H), 2.48-2.27 (m, 1H), 2.06-1.96 (m, 1H). D369 621.3 ¹HNMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.1 (d, 2H, TFA), 7.77 (dd, J =11.4, 7.3 Hz, 2H), 7.69 (s, 1H), 7.58 (d, J = 7.9 Hz, 1H), 6.78 (d, J =3.3 Hz, 2H), 5.13 (dd, J = 13.2, 5.1 Hz, 1H), 4.53-4.08 (m, 9H), 3.90(s, 6H), 3.51 (s, 3H), 2.93 (q, J = 9.5 Hz, 3H), 2.77-2.56 (m, 3H),2.40- 2.24 (m, 1H), 1.99 (q, J = 7.5 Hz, 3H). D370 651.3 ¹H NMR (300MHz, DMSO-d6) δ 11.01 (s, 1H), 8.15 (.1.0 FA, s, 1H), 7.99 (s, 1H),7.73-7.54 (m, 3H), 6.67 (s, 2H), 5.32-5.05 (m, 3H), 5.00-4.86 (m, 2H),4.58-4.27 (m, 2H), 3.84 (s, 6H), 3.67 (s, 2H), 3.56 (s, 3H), 3.01- 2.79(m, 3H), 2.75-2.55 (m, 2H), 2.47-2.20 (m, 3H), 2.11-1.95 (m, 1H),1.95-1.80 (m, 2H), 1.76-1.53 (m, 2H). D371 649.35 ¹H NMR (300 MHz,DMSO-d6) δ 11.01 (s, 1H), 8.19 (.1.0 FA, s, 1H), 7.75 (s, 1H), 7.68-7.55(m, 3H), 6.66 (s, 2H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.59-4.25 (m,2H), 3.81 (s, 6H), 3.54 (s, 2H), 3.51 (s, 3H), 3.01-2.87 (m, 3H),2.82-2.67 (m, 4H), 2.67-2.54 (m, 2H), 2.48-2.34 (m, 1H), 2.34-2.17 (m,2H), 2.08-1.91 (m, 3H), 1.91-1.77 (m, 2H), 1.69-1.50 (m, 2H). D372 765.6¹H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.17 (s, FA, 1H), 7.99 (s,1H), 7.37 (d, J = 8.2 Hz, 1H), 6.67 (s, 4H), 5.21 (s, 2H), 5.08 (dd, J =13.2, 5.0 Hz, 1H), 4.94 (s, 2H), 4.35-4.14 (m, 2H), 3.83 (s, 6H), 3.67(s, 2H), 3.57 (d, J = 3.8 Hz, 7H), 3.05-2.79 (m, 4H), 2.64-2.55 (m, 1H),2.42- 2.17 (m, 6H), 2.17-2.06 (m, 2H), 2.04-1.91 (m, 1H), 1.84-1.58 (m,6H), 1.58-1.47 (m, 1H), 1.28-0.95 (m, 2H). D373 642.2 ¹H NMR (300 MHz,DMSO-d6) δ 11.09 (s, 1H), 8.14 (s, FA, 0.2H), 8.00 (s, 1H), 7.68 (d, J =8.5 Hz, 1H), 7.38-7.17 (m, 2H), 6.68 (s, 2H), 5.21 (s, 2H), 5.07 (dd, J= 12.7, 5.4 Hz, 1H), 4.93 (s, 2H), 3.85 (s, 6H), 3.56 (s, 5H), 3.50-3.38(m, 4H), 2.97-2.80 (m, 1H), 2.69-2.54 (m, 4H), 2.50- 2.40 (m, 2H),2.11-1.95 (m, 1H). D374 528.1 ¹H NMR (300 MHz, DMSO-d6) δ 11.00 (s, 1H),7.82 (s, 1H), 7.67-7.42 (m, 3H), 6.78 (s, 2H), 5.13 (dd, 1H), 4.53-4.29(m, 2H), 3.73 (s, 6H), 3.53 (s, 3H), 3.08-2.99 (m, 2H), 2.69 (d, 4H),2.28 (s, 1H), 2.13-1.96 (m, 3H). D375 612.25 ¹H NMR (400 MHz, DMSO-d6) δ10.28 (s, 1H), 8.22 (s, 2H, FA), 7.74 (s, 1H), 7.14 (t, J = 8.0 Hz, 1H),6.64 (s, 2H), 6.58 (d, J = 7.9 Hz, 1H), 6.35 (s, 1H), 6.28 (d, J = 8.4Hz, 1H), 3.80 (s, 6H), 3.72 (t, J = 6.7 Hz, 2H), 3.50 (d, J = 3.4 Hz,6H), 2.96 (t, J = 7.5 Hz, 2H), 2.81-2.66 (m, 5H), 2.66-2.59 (m, 1H),2.40 (s, 4H), 2.03-1.92 (m, 3H), 1.69 (t, J = 5.5 Hz, 4H).

Example 68—BRD9 bromodomain TR-FRET Competition Binding Assay

This example demonstrates the ability of the compounds of the disclosureto biochemically inhibit BRD9 bromodomain in a competition bindingassay.

Procedure: His-Flag-BRD9 (P133-K239; Swiss Prot Q9H8M2; SEQ ID NO:1mgsshhhhhhenlyfq/gdykddddkgslevlfqg/PAENESTPIQQLLEHFLRQLQRKDPHGFFAFPVTDAIAPGYSMIIKHPMDFGTMKDKIVANEYKSVTEFKADFKLMCDNAMTYNRPDTVYYKLAKKILHAGFKMMSK) wascloned, expressed, purified, and then treated with TEV protease. CleavedHis tag was removed by purification. The binding of a biotinylated smallmolecule ligand of BRD9 was assessed via the LANCE® TR-FRET platform(PerkinElmer), and the compounds were assayed for inhibitory activityagainst this interaction.

Results: A mixture of biotinylated-ligand and SureLight™Allophycocyanin-Streptavidin (APC-SA, PerkinElmer AD0201) in 50 mM HEPES(pH 7.4), 50 mM NaCl, 1 mM TCEP (pH 7), 0.01% (v/v) Tween-20, 0.01%(w/v) bovine serum albumin was added to a white 384-well PerkinElmerProxiplate Plus plate. DMSO or 3-fold serially diluted compounds werethen added to the Proxiplate followed by addition of Flag-BRD9. After a10-minute incubation at room temperature, Eu-W1024 anti-FLAG(PerkinElmer, AD0273) was added. The final reaction mixture thatcontained 3.75 nM biotinylated ligand, 3 nM Flag-BRD9, 7.5 nM SureLight™Allophycocyanin-Streptavidin, and 0.2 nM Eu-W1024 anti-FLAG wasincubated at room temperature for 90 minutes.

The plates were then read on a PerkinElmer Envision plate reader todetermine the ratio of emission at 665 nm over 615 nm. Data wasnormalized to a DMSO control (100%) and a no protein control (0%) andthen fit to a four parameter, non-linear curve fit to calculate an IC₅₀(μM) as shown in Table 5. As shown by the results in Table 5, a numberof compounds of the present disclosure exhibit an IC₅₀ value of <1 μMfor BRD9 binding, indicating their affinity for targeting BRD9.

TABLE 5 Bromodomain TR-FRET Binding Compound No. Bromodomain TR-FRETBRD9 IC₅₀ (nM) B1 NT B2 + B3 + B4 + B5 ++++ B6 ++ B7 ++++ B8 +++ B9 ++++ B10 +  B11 +  B12 +  B13 +++  B14 +  B15 +  B16 +  B17 +  B18 +++  B19+++  B20 +++  B21 ++ D1 NT D2 NT D3 NT D4 NT D5 NT D6 NT D7 NT D8 NT D9NT  D10 NT  D11 NT  D12 NT  D13 NT  D14 +++  D15 +++  D16 NT  D17 +++ D18 +++  D19 +  D20 +  D21 +++  D22 ++++  D23 ++  D24 ++  D25 NT  D26++++  D27 ++  D28 ++++  D29 ++++  D30 ++  D31 ++++  D32 ++  D33 +++  D34+++  D35 +++  D36 +++  D37 ++++  D38 ++++ “+” indicates inhibitoryeffect of ≥1000 nM; “++” indicates inhibitory effect of ≥100 nM; “+++”indicates inhibitory effect of ≥10 nM; “++++” indicates inhibitoryeffect of <10 nM; “NT” indicates not tested

Example 69—SYO1 BRD9 NanoLuc Degradation Assay

This example demonstrates the ability of the compounds of the disclosureto degrade a Nanoluciferase-BRD9 fusion protein in a cell-baseddegradation assay.

Procedure: A stable SYO-1 cell line expressing 3×FLAG-NLuc-BRD9 wasgenerated. On day 0 cells were seeded in 30 μL media into each well of384-well cell culture plates. The seeding density was 8000 cells/well.On day 1, cells were treated with 30 nL DMSO or 30 nL of 3-fold seriallyDMSO-diluted compounds (10 points in duplicates with 1 μM as final topdose). Subsequently plates were incubated for 6 hours in a standardtissue culture incubator and equilibrated at room temperature for 15minutes. Nanoluciferase activity was measured by adding 15 μL of freshlyprepared Nano-Glo Luciferase Assay Reagent (Promega N₁₁₃₀), shaking theplates for 10 minutes and reading the bioluminescence using an EnVisionreader.

Results: The Inhibition % was calculated using the following formula: %Inhibition=100×(LumHC−Lum_(sample))/(Lum_(HC)−Lum_(LC)). DMSO treatedcells are employed as High Control (HC) and 1 μM of a known BRD9degrader standard treated cells are employed as Low Control (LC). Thedata was fit to a four parameter, non-linear curve fit to calculate IC₅₀(μM) values as shown in Table 6A, Table 6B, and Table 6C. As shown bythe results in Table 6A, Table 6B, and Table 6C, a number of compoundsof the present disclosure exhibit an IC₅₀ value of <1 μM for thedegradation of BRD9, indicating their use as compounds for reducing thelevels and/or activity of BRD9 and their potential for treatingBRD9-related disorders.

TABLE 6A SYO1 BRD9-NanoLuc Degradation Compound No. SYO1 BRD9-NanoLucdegradation IC₅₀ (nM) D1 +++ D2 +++ D3 ++ D4 +++ D5 + D6 ++ D7 +++ D8 ++D9 ++++  D10 ++  D11 +++  D12 +++  D13 +  D14 ++  D15 ++  D16 +++  D17+++  D18 +++  D19 +  D20 +  D21 +++  D22 ++++  D23 +  D24 +  D25 ++++ D26 NT  D27 NT  D28 ++++  D29 ++++  D30 +  D31 +++  D32 ++  D33 +  D34NT  D35 NT  D36 NT  D37 +++  D38 +++ “+” indicates inhibitory effect of≥1000 nM; “++” indicates inhibitory effect of ≥100 nM; “+++” indicatesinhibitory effect of ≥10 nM; “++++” indicates inhibitory effect of <10nM; “NT” indicates not tested

TABLE 6B SYO1 BRD9-NanoLuc Degradation Compound SYO1 BRD9-NanoLuc No.degradation IC₅₀ (nM) B22 + B23 + B24 NT D39 ++++ D40 ++++ D41 ++++ D42++++ D43 ++++ D44 ++++ D45 ++++ D46 ++++ D47 ++++ D48 ++++ D49 ++++ D50+++ D51 ++++ D52 ++++ D53 +++ D54 + D55 ++++ D56 ++++ D57 +++ D58 ++++D59 +++ D60 ++ D61 ++ D62 + D63 ++++ D64 ++++ D65 ++ D66 ++++ D67 ++ D68++++ D69 ++++ D70 + D71 ++++ D72 ++++ D73 ++++ D74 + D75 +++ D76 ++++D77 +++ D78 ++++ D79 + D80 ++++ D81 ++++ D82 ++++ D83 ++++ D84 ++++ D85++++ D86 ++++ D87 ++++ D88 ++++ D89 ++++ D90 +++ D91 ++++ D92 +++ D93++++ D94 NT D95 ++++ D96 ++++ D97 ++++ D98 ++++ D99 ++++ D100 ++++ D101++++ D102 ++++ D103 ++++ D104 ++++ D105 ++++ D106 ++++ D107 ++++ D109++++ D110 ++++ D111 +++ D112 ++++ D113 ++++ D114 ++++ D115 ++++ D116++++ D117 ++++ D118 ++++ D119 ++++ D120 ++ D121 ++++ D122 +++ D123 ++++D124 ++++ D125 ++++ D126 ++ D127 ++++ D128 ++++ D129 +++ D130 ++++ D131++++ D132 ++++ D133 ++++ D134 ++++ D135 ++++ D136 ++++ D137 +++ D138++++ D139 ++++ D140 ++++ D141 ++++ D142 ++++ D143 ++++ D144 +++ D145++++ D146 ++++ D147 ++++ D148 +++ D149 ++++ D150 +++ D151 ++++ D152 ++++D153 +++ D154 ++++ D155 ++++ D156 ++++ D157 ++++ D158 ++++ D159 ++++D161 ++++ D162 ++++ D163 ++++ D164 ++++ D165 ++++ D166 ++++ D167 +++D168 +++ D169 ++++ D170 ++++ D171 ++++ D172 ++++ D173 ++++ D174 ++++D175 ++ D176 +++ D177 +++ D178 ++++ D179 ++++ D180 ++++ D181 ++++ D182++++ D183 ++++ D184 +++ D185 ++ D186 +++ D187 +++ D188 ++ D189 ++ D190++ D191 ++ D192 ++ D193 + D194 ++ D195 ++++ D196 ++++ D197 ++++ D198++++ D199 ++++ D200 ++++ D201 ++++ D202 +++ D203 +++ D204 ++ D205 +++D206 ++ D207 +++ D208 +++ D209 +++ D210 +++ D211 ++ D212 +++ D213 ++D214 ++ D215 ++ D216 + D217 + D218 +++ D219 ++ D220 ++ D221 ++ D222 ++++D223 +++ D224 ++++ D225 +++ D226 +++ D227 ++++ D228 +++ D229 +++ D230 +D231 ++++ D232 +++ D233 ++ D234 +++ D235 ++ D236 +++ D237 + D238 +++D239 +++ D240 ++ D241 ++ D242 ++ D243 + D244 ++ D245 ++ D246 ++++ D247++ D248 + D249 + D250 ++ D251 ++++ D252 ++ D253 ++++ D254 ++++ D255 ++++D256 ++++ D257 + D258 ++ D259 +++ D260 +++ D261 +++ D262 ++ D263 ++D264 + D265 ++ D266 +++ D267 +++ D268 +++ D269 +++ D270 ++ D271 +++ D272++ D273 ++ D274 ++ D275 +++ D276 +++ D277 ++ D278 +++ D279 ++ D280 ++D281 +++ D282 ++ D283 ++++ D284 +++ D285 NT D286 ++ D287 ++ D288 ++ D289+++ D290 + D291 +++ D292 ++ D293 ++ D294 + D295 ++ D296 + D297 + D298 +D299 ++++ D300 ++++ D301 ++++ D302 ++++ DD1 ++++ “+” indicatesinhibitory effect of ≥ 1000 nM; “++” indicates inhibitory effect of ≥100 nM; “+++” indicates inhibitory effect of ≥ 10 nM; “++++” indicatesinhibitory effect of < 10 nM; “NT” indicates not tested

TABLE 6C SYO1 BRD9-NanoLuc Degradation Compound SYO1 BRD9-NanoLuc No.degradation IC₅₀ (nM) D303 ++++ D304 ++++ D305 + D306 ++++ D307 ++++D308 ++++ D309 ++++ D310 ++++ D311 ++++ D312 ++++ D313 + D314 ++++ D315++++ D316 + D317 ++++ D318 ++++ D319 ++++ D320 ++++ D321 ++++ D322 ++++D323 ++++ D324 ++++ D325 ++++ D326 ++++ D327 ++++ D328 + D329 ++++ D330++++ D331 +++ D332 ++++ D333 ++++ D334 ++++ D335 ++++ D336 ++++ D337 +D338 ++++ D339 ++++ D340 ++++ D341 ++++ D342 ++++ D343 + D344 ++++ D345++++ D346 ++++ D347 ++++ D348 ++++ D349 +++ D350 ++++ D351 +++ D352 +++D353 ++++ D354 ++++ D355 ++++ D356 ++++ D357 ++++ D358 ++++ D359 ++++D360 ++++ D361 ++++ D362 ++++ D363 ++++ D364 ++++ D365 ++++ D366 ++++D367 ++++ D368 ++++ D369 ++++ D370 ++++ D371 ++++ D372 ++++ D373 ++++D374 ++++ D375 + “+” indicates inhibitory effect of ≥ 1000 nM; “++”indicates inhibitory effect of ≥ 100 nM; “+++” indicates inhibitoryeffect of ≥ 10 nM; “++++” indicates inhibitory effect of < 10 nM; “NT”indicates not tested

Other Embodiments

All publications, patents, and patent applications mentioned in thisspecification are incorporated herein by reference in their entirety tothe same extent as if each individual publication, patent, or patentapplication was specifically and individually indicated to beincorporated by reference in its entirety. Where a term in the presentapplication is found to be defined differently in a documentincorporated herein by reference, the definition provided herein is toserve as the definition for the term.

While the invention has been described in connection with specificembodiments thereof, it will be understood that invention is capable offurther modifications and this application is intended to cover anyvariations, uses, or adaptations of the invention following, in general,the principles of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

Other embodiments are in the claims.

1. A compound having the structure of Formula I:

wherein R¹ is H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₁₀ carbocyclyl; Z¹ is CR² or N; R² is H,halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl, oroptionally substituted C₂-C₉ heteroaryl;

X¹ is a bond, O, NR^(3a),

 or CR^(4a)R^(5a); X² is O, NR^(3b),

 or CR^(4b)R^(5b); X³ is O, NR^(3c),

 or CR^(4c)R^(5c); X⁴ is a bond, O, NR^(3d),

 or CR^(4d)R^(5d); X⁵ is O or NR^(3e) and X⁶ is CR^(4f)R^(5f), or X⁵ isCR^(4e)R^(5e) and X⁶ is O or NR^(3f); X⁷ is O, NR^(3g), orCR^(4g)R^(5g); X⁸ is O, NR^(3h), or CR^(4h)R^(5h); each of R^(3a),R^(3b), R^(3c), and R^(3d) is, independently, H, halogen, hydroxyl,optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted C₁-C₆ acyl, thiol, optionally substituted sulfone,optionally substituted sulfonamide, or optionally substituted amino, orR^(3a) and R^(4b), R^(4a) and R^(3b), R^(4b) and R^(4a), R^(3b) andR^(4c), R^(4b) and R^(4c), R^(3c) and R^(4b), R^(3c) and R^(4d), R^(4c)and R^(4d), and/or R^(3d) and R^(4c), together with the atoms to whicheach is attached, combine to form optionally substituted C₂-C₉heterocyclyl; each of R^(4a), R^(4b), R^(4c), and R^(4d) is,independently, H, halogen, hydroxyl, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, or optionally substituted amino, or R^(3a) andR^(4b), R^(4a) and R^(3b), R^(4b) and R^(4a), R^(3b) and R^(4c), R^(4b)and R^(4c), R^(3c) and R^(4b), R^(3c) and R^(4d), R^(4c) and R^(4d),and/or R^(3d) and R^(4c), together with the atoms to which each isattached, combine to form optionally substituted C₂-C₉ heterocyclyl;each of R^(5a), R^(5b), R^(5c), and R^(5d) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxyl, thiol, or optionally substituted amino; each ofR^(3e), R^(3f), R^(3g), and R^(3h) is, independently, H, halogen,hydroxyl, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted C₁-C₆ acyl, thiol, optionally substituted sulfone,optionally substituted sulfonamide, or optionally substituted amino, orR^(3e) and R^(4f) or R^(4e) and R^(3f), together with the atoms to whicheach is attached, combine to form optionally substituted heterocyclycl;each of R^(4e), R^(4f), R^(4g), and R^(4h) is, independently, H,halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3e) and R^(4f) or R^(4e) and R^(3f), togetherwith the atoms to which each is attached, combine to form optionallysubstituted heterocyclycl; each of R^(5e), R^(5f), R^(5g), and R^(5h)is, independently, H, halogen, hydroxyl, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxyl, thiol, or optionally substituted amino;and G is optionally substituted C₆-C₁₀ aryl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1, wherein


3. A compound having the structure of Formula II:A-L-B   Formula II, where B is a degradation moiety, L is a linker, andA has the structure of Formula III:

where R¹ is H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₁₀ carbocyclyl; Z¹ is CR² or N; R² is H,halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl, oroptionally substituted C₂-C₉ heteroaryl;

X¹′ is a bond, O, NR^(3a)′, or CR^(4a)′R^(5a); X²′ is O, NR^(3b)′, orCR^(4b)′R^(5b)′; X³′ is O, NR^(3c)′, or CR^(4c)′R^(5c)′; X⁴′ is a bond,O, NR^(3d)′, or CR^(4d)′R^(5d)′; X⁵′ is O, NR^(3e)′, or CR^(4e)′R^(5e)′;X⁶′ is O, NR^(3f)′, or CR^(4f)′R^(5f)′; X⁷′ is O, NR^(3g)′, orCR^(4g)′R^(5g)′; each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H,

 halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3a)′ and R^(4b)′, R^(4a)′ and R^(3b)′, R^(4b)′and R^(4a)′, R^(3b)′ and R^(4c)′, R^(4b)′ and R^(4c)′, R^(3c)′ andR^(4b)′, R^(3c)′ and R^(4d)′, R^(4c)′ and R^(4d)′, and/or R^(3d)′ andR^(4c)′, together with the atoms to which each is attached, combine toform optionally substituted C₂-C₉ heterocyclyl; R³′ is absent,optionally substituted C₁-C₆ alkylene, optionally substituted C₁-C₆heteroalkylene, optionally substituted C₃-C₁₀ carbocyclylene, optionallysubstituted C₂-C₉ heterocyclylene, optionally substituted C₆-C₁₀arylene, optionally substituted C₂-C₉ heteroarylene, optionallysubstituted C₂-C₆ alkenylene, optionally substituted C₂-C₆heteroalkenylene, optionally substituted sulfone, optionally substitutedsulfonamide, or optionally substituted amino; each of R^(4a)′, R^(4b),R^(4′), and R^(4d)′ is, independently, H, halogen, hydroxyl, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl,optionally substituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₂-C₉ heteroaryl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ heteroalkenyl, thiol, optionally substituted sulfone,or optionally substituted amino, or R^(3a)′ and R^(4b)′, R^(4a)′ andR^(3b)′, R^(4b)′ and R^(4a)′, R^(3b)′ and R^(4c)′, R^(4b)′ and R^(4c)′,R^(3c)′ and R^(4b)′, R^(3c)′ and R^(4d)′, R^(4c)′ and R^(4d)′, and/orR^(3d)′ and R^(4c)′, together with the atoms to which each is attached,combine to form optionally substituted C₂-C₉ heterocyclyl; each ofR^(5a)′, R^(5b)′, R^(5c)′, and R^(5d)′ is, independently, H, halogen,hydroxyl, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, hydroxyl, thiol, oroptionally substituted amino; each of R^(3e)′, R^(3f)′, and R^(3g)′ is,independently, H,

 halogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3e) and R^(4f) or R^(4e) and R^(3f), togetherwith the atoms to which each is attached, combine to form optionallysubstituted heterocyclycl; each of R^(4e)′, R^(4f)′, and R^(4g)′ is,independently, H, halogen, hydroxyl, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted C₁-C₆ acyl, thiol, optionallysubstituted sulfone, optionally substituted sulfonamide, or optionallysubstituted amino, or R^(3e)′ and R^(4f)′ or R^(4e)′ and R^(3f)′,together with the atoms to which each is attached, combine to formoptionally substituted heterocyclycl; each of R^(5e)′, R^(5f)′, andR^(5g)′ is, independently, H, halogen, hydroxyl, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₂-C₉ heteroaryl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ heteroalkenyl, hydroxyl, thiol, or optionallysubstituted amino; G″ is

 optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl; G′ is optionally substituted C₃-C₁₀ carbocyclylene, C₂-C₉heterocyclylene, optionally substituted C₆-C₁₀ arylene, or optionallysubstituted C₂-C₉ heteroarylene; and A¹ is a bond between A and thelinker, where one of R^(3a)′, R^(3b)′, R^(3c)′, R^(3d)′, R^(3e)′,R^(3f)′, and R^(3g)′ is

 or G is

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim3, wherein


5. The compound of claim 4, wherein


6. The compound of any one of claims 1 to 5, wherein R¹ is H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, oroptionally substituted C₃-C₁₀ carbocyclyl.
 7. The compound of claim 6,wherein R¹ is H.
 8. The compound of claim 6, wherein R¹ is optionallysubstituted C₁-C₆ alkyl.
 9. The compound of claim 8, wherein R¹ is


10. The compound of claim 6, wherein R¹ is optionally substituted C₂-C₆alkenyl.
 11. The compound of claim 10, wherein R¹ is


12. The compound of claim 6, wherein R¹ is optionally substituted C₃-C₁₀carbocyclyl.
 13. The compound of claim 12, wherein R¹ is


14. The compound of claim 6, wherein R¹ is H or


15. The compound of any one of claims 1 to 14, wherein Z¹ is N.
 16. Thecompound of any one of claims 1 to 14, wherein Z¹ is CR².
 17. Thecompound of claim 16, wherein R² is H, halogen, optionally substitutedC₁-C₆ alkyl, optionally substituted C₃-C₁₀ carbocyclyl, or optionallysubstituted C₆-C₁₀ aryl.
 18. The compound of claim 17, wherein R² is H,halogen, or optionally substituted C₁-C₆ alkyl.
 19. The compound ofclaim 18, wherein R² is H, F, or


20. The compound of any one of claims 3 to 19, wherein X¹′ is a bond.21. The compound of any one of claims 3 to 19, wherein X¹′ is O,NR^(3a)′, or CR^(4a)′R^(5a)′.
 22. The compound of any one of claims 3 to21, wherein X²′ is NR^(3b)′ or CR^(4b)′R^(5b)′.
 23. The compound ofclaim 22, wherein X²′ is NR^(3b)′.
 24. The compound of any one of claims3 to 23, wherein X³′ is NR^(3c)′ or CR^(4c)′R^(5c)′.
 25. The compound ofany one of claims 3 to 24, wherein X⁴′ is a bond.
 26. The compound ofany one of claims 3 to 24, wherein X⁴′ is O, NR^(3b)′, orCR^(4b)′R^(5b)′.
 27. The compound of any one of claims 3 to 26, whereinX¹′ is CR^(4a)′R^(5a)′; X²′ is NR^(3b)′; X³′ is CR^(4c)′R^(5c)′; and X⁴′is CR^(4d)′R^(5d)′.
 28. The compound of any one of claims 3 to 26,wherein X¹′ is CR^(4a)′R^(5a)′; X²′ is CR^(4b)′R^(5b)′; X³′ is NR^(3c)′;and X⁴′ is CR^(4d)′R^(5d)′.
 29. The compound of any one of claims 3 to26, wherein X¹′ is O or NR^(3a)′; X²′ is CR^(4b)′R^(5b)′; X³′ isCR^(4c)′R^(5c)′; and X⁴′ is O or NR^(3d)′.
 30. The compound of any oneof claims 3 to 26, wherein X¹′ is a bond; X²′ is CR^(4b)′R^(5b)′; X³′ isO or NR^(3c)′; and X⁴′ is CR^(4d)′R^(5d)′.
 31. The compound of any oneof claims 3 to 26, wherein X¹′ is CR^(4a)′R^(5a)′; X²′ isCR^(4b)′R^(5b)′; X³′ is CR^(4c)′R^(5c)′; and X⁴′ is CR^(4d)′R^(5d)′. 32.The compound of any one of claims 3 to 26, wherein X⁵′ isCR^(4e)′R^(5e)′ and X⁶′ is NR^(3f)′.
 33. The compound of any one ofclaims 3 to 32, wherein each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′is, independently, H,

optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₁-C₆ acyl, optionally substitutedsulfone, or optionally substituted sulfonamide.
 34. The compound ofclaim 33, wherein each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H,

optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, or optionally substituted C₁-C₆ acyl.
 35. The compound ofclaim 33, wherein each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H,

optionally substituted C₁-C₆ alkyl,

wherein R⁶ is H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, or optionally substituted C₆-C₁₀ aryl; W¹ is O or S; W² isNR⁷ or O; R⁷ is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl; R⁸ is optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, or optionally substituted C₆-C₁₀ aryl; and R⁹ is H,optionally substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆heteroalkyl.
 36. The compound of claim 35, wherein each of R^(3a)′,R^(3b)′, R^(3c)′, and R^(3d)′ is, independently, H,

optionally substituted C₁-C₆ alkyl,

wherein R⁶ is H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, or optionally substituted C₆-C₁₀ aryl; W¹ is O or S; and W²is NR⁷ or O.
 37. The compound of claim 36, wherein each of R^(3a)′,R^(3b)′, R^(3c)′, and R^(3d)′ is, independently, H,

C₁-C₆ alkyl, or


38. The compound of any one of claims 35 to 37, wherein each of R^(3a)′,R^(3b)′, R^(3c)′, and R^(3d)′ is, independently,


39. The compound of any one of claims 3 to 38, wherein each of R^(4a)′,R^(4b)′, R^(4c)′, and R^(4d)′ is, independently, H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl,optionally substituted C₁-C₆ acyl, optionally substituted sulfone, oroptionally substituted sulfonamide.
 40. The compound of claim 39,wherein each of R^(4a)′, R^(4b)′, R^(4c)′, and R^(4d)′ is,independently, H, optionally substituted C₁-C₆ alkyl,

wherein R⁶ is H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, or optionally substituted C₆-C₁₀ aryl; W¹ is O or S; W² isNR⁷ or O; R⁷ is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl; R⁸ is optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, or optionally substituted C₆-C₁₀ aryl; and R⁹ is H,optionally substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆heteroalkyl.
 41. The compound of claim 40, wherein each of R^(4a)′,R^(4b)′, R^(4c)′, and R^(4d)′ is, independently, H or optionallysubstituted C₁-C₆ alkyl.
 42. The compound of claim 41, wherein each ofR^(4a)′, R^(4b)′, R^(4c)′, and R^(4d)′ is H.
 43. The compound of any oneof claims 35 to 42, wherein W¹ is O.
 44. The compound of any one ofclaims 35 to 43, wherein W² is NR⁷.
 45. The compound of any one ofclaims 35 to 44, wherein R⁶ is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, or optionally substitutedC₃-C₁₀ carbocyclyl.
 46. The compound of claim 35, wherein R⁶ is H,methyl, ethyl,


47. The compound of any one of claims 35 to 46, wherein R⁷ is H oroptionally substituted C₁-C₆ alkyl.
 48. The compound of claim 47,wherein R⁷ is H or methyl.
 49. The compound of any one of claims 35 to48, wherein each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H,


50. The compound of any one of claims 3 to 49, wherein each of R^(5a)′,R^(5b)′, R^(5c)′, and R^(5d)′ is, independently, H, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl.51. The compound of claim 50, wherein each of R^(5a)′, R^(5b)′, R^(5c)′,and R^(5d)′ is H.
 52. The compound of any one of claims 3 to 51, whereinone of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is


53. The compound of claim 52, wherein R^(3b)′ is


54. The compound of claim 52, wherein R^(3c)′ is


55. The compound of any one of claims 52 to 54, wherein R³′ is absent.56. The compound of any one of claims 3 to 55, wherein each of R^(3e)′,R^(3f)′, and R^(3g)′ is, independently H,

optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₁-C₆ acyl, optionally substitutedsulfone, or optionally substituted sulfonamide.
 57. The compound of anyone of claims 3 to 56, wherein each of R^(4e)′, R^(4f)′, and R^(4g)′ is,independently, H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₁-C₆ acyl,optionally substituted sulfone, or optionally substituted sulfonamide.58. The compound of any one of claims 3 to 57, wherein each of R^(5e)′,R^(5f)′, and R^(5g)′ is, independently, H, optionally substituted C₁-C₆alkyl, or optionally substituted C₁-C₆ heteroalkyl.
 59. The compound ofany one of claims 32 to 58, wherein G″ is optionally substituted C₆-C₁₀aryl, optionally substituted C₃-C₁₀ carbocyclyl, optionally substitutedC₂-C₉ heteroaryl, or C₂-C₉ heterocyclyl.
 60. The compound of claim 59,wherein G″ is optionally substituted C₆-C₁₀ aryl or optionallysubstituted C₂-C₉ heteroaryl.
 61. The compound of claim 60, wherein G″is optionally substituted C₆-C₁₀ aryl.
 62. The compound of claim 1,wherein G″ is

wherein each of R^(G1), R^(G2), R^(G3), R^(G4), and R^(G5) is,independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₆-C₁₀aryl, optionally substituted C₃-C₁₀ carbocyclyl, optionally substitutedC₂-C₉ heteroaryl, or optionally substituted C₂-C₉ heterocyclyl.
 63. Thecompound of claim 62, wherein each of R^(G1), R^(G2), R^(G3), R^(G4),and R^(G5) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl; or R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heteroaryl or optionally substituted C₂-C₉ heterocyclyl.
 64. Thecompound of claim 63, wherein each of R^(G1), R^(G2), R^(G3), R^(G4),and R^(G5) is, independently, H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.
 65. The compound of claim 64, wherein each of R^(G1),R^(G2), R^(G3), R^(G4), and R^(G5) is, independently, H, F, Cl,


66. The compound of claim 65, wherein each of R^(G1), R^(G2), R^(G3),R^(G4), and R^(G5) is, independently, H, F,


67. The compound of claim 66, wherein each of R^(G1), R^(G2), R^(G3),R^(G4), and R^(G5) is, independently, H, F, Cl,


68. The compound of claim 67, wherein two or more of R^(G1), R^(G2),R^(G3), R^(G4), and R^(G5) is H.
 69. The compound of claim 68, whereinR^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is

and R^(G5) is H.
 70. The compound of claim 68, wherein R^(G1) is H;R^(G2) is

R^(G3) is

R^(G4) is H; and R^(G5) is


71. The compound of claim 68, wherein R^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is Cl or F; and R^(G5) is H.
 72. The compound of claim 68,wherein R^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is H; and R^(G5) is H.
 73. The compound of claim 68, whereinR^(G1) is H; R^(G2) is

R^(G3) is

R^(G4) is

and R^(G5) is H.
 74. The compound of claim 63, wherein R^(G1) andR^(G2), R^(G2) and R^(G3), R^(G3) and R^(G4), and/or R^(G4) and R^(G5),together with the carbon atoms to which each is attached, combine toform optionally substituted C₂-C₉ heterocyclyl.
 75. The compound ofclaim 63, wherein R^(G1) and R^(G2), R^(G2) and R^(G3), R^(G3) andR^(G4), and/or R^(G4) and R^(G5), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₂-C₉heteroaryl.
 76. The compound of claim 74, wherein G″ is

wherein R^(G6) is H or optionally substituted C₁-C₆ alkyl.
 77. Thecompound of claim 75, wherein G″ is

wherein R^(G6)′ is H or optionally substituted C₁-C₆ alkyl
 78. Thecompound of claim 76 or 77, wherein R^(G6) is H or


79. The compound of claim 78, wherein R^(G6) is H.
 80. The compound ofclaim 61, wherein G″ is optionally substituted C₂-C₉ heteroaryl.
 81. Thecompound of claim 80, wherein G″ is

wherein each of R^(G7), R^(G8), R^(G9), R^(G10), and R^(G11) is,independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G7) and R^(G8), R^(G8) and R^(G9), R^(G9) andR^(G10), and/or R^(G10) and R^(G11), together with the carbon atoms towhich each is attached, combine to form optionally substituted C₆-C₁₀aryl, optionally substituted C₃-C₁₀ carbocyclyl, optionally substitutedC₂-C₉ heteroaryl, or C₂-C₉ heterocyclyl.
 82. The compound of claim 81,wherein each of R^(G7), R^(G8), R^(G9), R^(G10), and R^(G11) is,independently, H, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, or optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl.
 83. The compound of claim 81 or 82, wherein G″ is


84. The compound of claim 83, wherein R^(G7) is H; R^(G8) is

R^(G9) is H; and R^(G11) is H.
 85. The compound of claim 80, wherein G″is

wherein each of R^(G12), R^(G13), and R^(G14) is, independently, H,halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G12) and R^(G14), together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.
 86. The compound of anyone of claims 3 to 51, wherein G″ is


87. The compound of claim 86, wherein G′ is optionally substitutedC₆-C₁₀ aryl or optionally substituted C₂-C₉ heteroaryl.
 88. The compoundof claim 87, wherein G′ is optionally substituted C₆-C₁₀ aryl.
 89. Thecompound of claim 88, wherein G′ is

wherein each of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, and R^(G5)′ is,independently, H, A¹, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G1)′ and R^(G2)′, R^(G2)′ and R^(G3)′, R^(G3)′and R^(G4)′, or R^(G4)′ and R^(G5)′, together with the carbon atoms towhich each is attached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or optionallysubstituted C₂-C₉ heterocyclyl, any of which is optionally substitutedwith A¹, wherein one of R^(G1)′, R^(G2)′, R^(G3), R^(G4)′, and R^(G5)′is A¹, or

is substituted with A¹.
 90. The compound of claim 89, wherein each ofR^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, and R^(G5)′ is, independently, H,A¹, halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted —O—C₃-C₆ carbocyclyl, oroptionally substituted —C₁-C₃ alkyl-C₂-C₅ heterocyclyl; or R^(G1)′ andR^(G2)′, R^(G2)′ and R^(G3)′, R^(G3)′ and R^(G4)′, and/or R^(G4)′ andR^(G5)′, together with the carbon atoms to which each is attached,combine to form

; and

is optionally substituted C₂-C₉ heteroaryl or optionally substitutedC₂-C₉ heterocyclyl, any of which is optionally substituted with A¹,wherein one of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, and R^(G5)′ is A¹, or

is substituted with A¹.
 91. The compound of claim 90, wherein each ofR^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, and R^(G5)′ is, independently, H,A¹, halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted —O—C₃-C₆ carbocyclyl, oroptionally substituted —C₁-C₃ alkyl-C₂-C₅ heterocyclyl.
 92. The compoundof claim 91, wherein each of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′, andR^(G5)′ is, independently, H, A¹, F, Cl,


93. The compound of claim 92, wherein each of R^(G1)′, R^(G2)′, R^(G3)′,R^(G4)′, and R^(G5)′ is, independently, H, A¹, F,


94. The compound of claim 93, wherein each of R^(G1)′, R^(G2)′, R^(G3)′,R^(G4)′, and R^(G5)′ is, independently, H, A¹, F, Cl,


95. The compound of claim 94, wherein R^(G3)′ is A¹.
 96. The compound ofclaim 95, wherein R^(G1)′ is H; R^(G2)′ is

R^(G3)′ is A¹; R^(G4)′ is

and R^(G5)′ is H.
 97. The compound of claim 95, wherein R^(G1)′ is H;R^(G2)′ is

R^(G3)′ is A¹; R^(G4)′ is H; and R^(G5)′ is


98. The compound of claim 95, wherein R^(G1)′ is H; R^(G2)′ is

R^(G3)′ is A¹; R^(G4)′ is Cl or F; and R^(G5)′ is H.
 99. The compound ofclaim 95, wherein R^(G1)′ is H; R^(G2)′ is

R^(G3)′ is A¹; R^(G4)′ is H; and R^(G5)′ is H.
 100. The compound ofclaim 95, wherein R^(G1)′ is H; R^(G2)′ is

R^(G3)′ is A¹; R^(G4)′ is

and R^(G5)′ is H.
 101. The compound of claim 90, wherein R^(G1)′ andR^(G2)′, R^(G2)′ and R^(G3)′, R^(G3)′ and R^(G4)′, and/or R^(G4)′ andR^(G5)′, together with the carbon atoms to which each is attached,combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A¹, wherein one of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′,and R^(G5)′ is A¹, or

is substituted with A¹.
 102. The compound of claim 90, wherein R^(G1)′and R^(G2)′, R^(G2)′ and R^(G3)′, R^(G3)′ and R^(G4)′, and/or R^(G4)′and R^(G5)′, together with the carbon atoms to which each is attached,combine to form

; and

is optionally substituted C₂-C₉ heteroaryl, which is optionallysubstituted with A¹, wherein one of R^(G1)′, R^(G2)′, R^(G3)′, R^(G4)′,and R^(G5)′ is A¹, or is substituted with A¹.
 103. The compound of claim101, wherein G′ is

wherein R^(G6)′ is H, A¹, or optionally substituted C₁-C₆ alkyl. 104.The compound of claim 102, wherein G′ is

wherein R^(G6)′ is H, A¹, or optionally substituted C₁-C₆ alkyl
 105. Thecompound of claim 103 or 104, wherein R^(G6)′ is H, A¹, or


106. The compound of claim 105, wherein R^(G6)′ is H.
 107. The compoundof claim 54, wherein G′ is optionally substituted C₂-C₉ heteroaryl. 108.The compound of claim 107, wherein G′ is

wherein each of R^(G7)′, R^(G8)′, R^(G9)′, R^(G10)′, and R^(G11)′ is,independently, H, A¹, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl, optionallysubstituted —C₁-C₃ alkyl-C₃-C₆ carbocyclyl, optionally substituted—C₁-C₃ alkyl-C₂-C₅ heterocyclyl, hydroxyl, thiol, or optionallysubstituted amino; or R^(G7)′ and R^(G8)′, R^(G8)′ and R^(G9)′, R^(G9)′and R^(G10)′, and/or R^(G10)′ and R^(G11)′, together with the carbonatoms to which each is attached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A¹, whereinone of R^(G7)′, R^(G8)′, R^(G9)′, R^(G10)′, and R^(G11)′ is A¹; or

is substituted with A¹.
 109. The compound of claim 108, wherein each ofR^(G7)′, R^(G8)′, R^(G9)′, R^(G10)′, and R^(G11)′ is, independently, H,A¹, halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted —O—C₃-C₆ carbocyclyl, oroptionally substituted —C₁-C₃ alkyl-C₂-C₅ heterocyclyl.
 110. Thecompound of claim 108 or 109, wherein G′ is


111. The compound of claim 110, wherein R^(G7)′ is H; R^(G8)′ is

R^(G9)′ is A¹; and R^(G11)′ is H.
 112. The compound of claim 107,wherein G′ is

wherein each of R^(G12)′, R^(G13)′, and R^(G14)′ is, independently, H,A¹, halogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₂-C₉ heterocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₂-C₉ heteroaryl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ heteroalkenyl, optionallysubstituted —O—C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃alkyl-C₃-C₆ carbocyclyl, optionally substituted —C₁-C₃ alkyl-C₂-C₅heterocyclyl, hydroxyl, thiol, or optionally substituted amino; orR^(G12)′ and R^(G14)′, together with the carbon atoms to which each isattached, combine to form optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heteroaryl,or optionally substituted C₂-C₉ heterocyclyl.
 113. The compound of anyone of claims 86 to 112, wherein each of R^(3a)′, R^(3b)′, R^(3c)′, andR^(3d)′ is, independently, H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₁-C₆acyl, optionally substituted sulfone, or optionally substitutedsulfonamide.
 114. The compound of claim 113 wherein each of R^(3a)′,R^(3b)′, R^(3c)′, and R^(3d)′ is, independently, H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₁-C₆ acyl.
 115. The compound of claim 113,wherein each of R^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is,independently, H, optionally substituted C₁-C₆ alkyl,

wherein R⁶ is H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, or optionally substituted C₆-C₁₀ aryl; W¹ is O or S; W² isNR⁷ or O; R⁷ is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl; R⁸ is optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, or optionally substituted C₆-C₁₀ aryl; and R⁹ is H,optionally substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆heteroalkyl.
 116. The compound of claim 114, wherein each of R^(3a)′,R^(3b)′, R^(3c)′, and R^(3d)′ is, independently, H, optionallysubstituted C₁-C₆ alkyl,

wherein R⁶ is H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, or optionally substituted C₆-C₁₀ aryl; W¹ is O or S; and W²is NR⁷ or O.
 117. The compound of claim 115 or 116, wherein each ofR^(3a)′, R^(3b)′, R^(3c)′, and R^(3d)′ is, independently, H, C₁-C₆alkyl, or


118. The compound of any one of claims 115 to 117, wherein each ofR^(3a)′, R^(3b)′, R^(3c)′ and R^(3d)′ is, independently,


119. The compound of any one of claims 115 to 118, wherein W¹ is O. 120.The compound of any one of claims 115 to 119, wherein W² is NR⁷. 121.The compound of any one of claims 115 to 120, wherein R⁶ is H,optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, or optionally substituted C₃-C₁₀ carbocyclyl.
 122. Thecompound of claim 115, wherein R⁶ is H, methyl, ethyl,


123. The compound of any one of claims 113 to 122, wherein R⁷ is H oroptionally substituted C₁-C₆ alkyl.
 124. The compound of claim 123,wherein R⁷ is H or methyl.
 125. The compound of any one of claims 113 to124, wherein each of R^(3a)′, R^(3b)′, R^(3c)′ and R^(3d)′ is,independently, H, methyl,


126. The compound of any one of claims 3 to 125, wherein A has thestructure of Formula IIIa:

or a pharmaceutically acceptable salt thereof.
 127. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIb:

or a pharmaceutically acceptable salt thereof.
 128. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIc:

or a pharmaceutically acceptable salt thereof.
 129. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIf:

or a pharmaceutically acceptable salt thereof.
 130. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIg:

or a pharmaceutically acceptable salt thereof.
 131. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIh:

or a pharmaceutically acceptable salt thereof.
 132. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIi:

or a pharmaceutically acceptable salt thereof.
 133. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIj:

or a pharmaceutically acceptable salt thereof.
 134. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIk:

or a pharmaceutically acceptable salt thereof.
 135. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIm:

or a pharmaceutically acceptable salt thereof.
 136. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIn:

or a pharmaceutically acceptable salt thereof.
 137. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIo:

or a pharmaceutically acceptable salt thereof.
 138. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIp:

or a pharmaceutically acceptable salt thereof.
 139. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIq:

or a pharmaceutically acceptable salt thereof.
 140. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIr:

or a pharmaceutically acceptable salt thereof.
 141. The compound of anyone of claims 3 to 125, wherein A has the structure of Formula IIIs:

or a pharmaceutically acceptable salt thereof.
 142. The compound of anyone of claims 3 to 141, wherein the degradation moiety is a ubiquitinligase binding moiety.
 143. The compound of claim 142, wherein theubiquitin ligase binding moiety comprises Cereblon ligands, IAP(Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2),or von Hippel-Lindau (VHL) ligands, or derivatives or analogs thereof.144. The compound of claim 142 or 143, wherein the degradation moietycomprises the structure of Formula Y:

where A² is a bond between the degradation moiety and the linker; v1 is0, 1, 2, 3, 4, or 5; u1 is 1, 2, or 3; T¹ is a bond or

T² is

R^(5A) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl; each R^(J1) is, independently, halogen,optionally substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆heteroalkyl; J^(A) is absent, O, optionally substituted amino,optionally substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆heteroalkyl; and J is absent, optionally substituted C₃-C₁₀carbocyclylene, optionally substituted C₆-C₁₀ arylene, optionallysubstituted C₂-C₉ heterocyclylene, or optionally substituted C₂-C₉heteroarylene, or a pharmaceutically acceptable salt thereof.
 145. Thecompound of claim 144, wherein T² is


146. The compound of claim 145, wherein T² is


147. The compound of claim 145, wherein T² is


148. The compound of any one of claims 144 to 147, wherein the structureof Formula Y has the structure of Formula Y1:

or a pharmaceutically acceptable salt thereof.
 149. The compound ofclaim 148, wherein T¹ is a bond.
 150. the compound of claim 148, whereinT¹ is


151. The compound of any one of claims 144 to 150, wherein the structureof Formula Y has the structure of Formula Y2:

or a pharmaceutically acceptable salt thereof.
 152. The compound of anyone of claims 144 to 150, wherein the structure of Formula Y has thestructure of Formula Z:

or a pharmaceutically acceptable salt thereof.
 153. The compound of anyone of claims 144 to 152, wherein u1 is
 2. 154. The compound of claim153, wherein the structure of Formula Z has the structure of FormulaAA0:

or a pharmaceutically acceptable salt thereof.
 155. The compound of anyone of claims 144 to 152, wherein u1 is
 1. 156. The compound of claim155, wherein the structure of Formula Z has the structure of Formula AB:

or a pharmaceutically acceptable salt thereof.
 157. The compound of anyone of claims 144 to 152, wherein u1 is
 3. 158. The compound of claim157, wherein the structure of Formula Z has the structure of Formula AC:

or a pharmaceutically acceptable salt thereof.
 159. The compound of anyone of claims 144 to 158, wherein J^(A) is absent.
 160. The compound ofany one of claims 144 to 158, wherein J^(A) is optionally substitutedC₁-C₆ alkyl.
 161. The compound of claim 160, wherein J^(A) is


162. The compound of claim 161, wherein the structure of Formula AA0 hasthe structure of Formula AA0:

or a pharmaceutically acceptable salt thereof.
 163. The compound of anyone of claims 144 to 162, wherein v1 is 0, 1, 2, or
 3. 164. The compoundof claim 163, wherein v1 is
 0. 165. The compound of claim 164, whereinthe structure of Formula AA has the structure of Formula AA1:

or a pharmaceutically acceptable salt thereof.
 166. The compound of anyone of claims 144 to 165, wherein R^(A5) is H or optionally substitutedC₁-C₆ alkyl.
 167. The compound of claim 166, wherein R^(A5) is H. 168.The compound of claim 166, wherein R^(A5) is methyl.
 169. The compoundof any one of claims 144 to 165, wherein R^(A5) is optionallysubstituted C₁-C₆ heteroalkyl.
 170. The compound of claim 169, whereinR^(A5) is


171. The compound of claim 162, wherein the structure of Formula AA hasthe structure of Formula AA1:

or a pharmaceutically acceptable salt thereof.
 172. The compound ofclaim 156, wherein the structure of Formula AB has the structure ofFormula AB1:

or a pharmaceutically acceptable salt thereof.
 173. The compound ofclaim 158, wherein the structure of Formula AC has the structure ofFormula AC1:

or a pharmaceutically acceptable salt thereof.
 174. The compound of anyone of claims 171 to 173, wherein J is absent.
 175. The compound ofclaim 174, wherein the structure of Formula AA1 has the structure ofFormula AA2:

or a pharmaceutically acceptable salt thereof.
 176. The compound of anyone of claims 171 to 173, wherein J is optionally substituted C₃-C₁₀carbocyclylene or optionally substituted C₆-C₁₀ arylene.
 177. Thecompound of claim 176, wherein the structure of Formula AA has thestructure of Formula AA4:

or a pharmaceutically acceptable salt thereof.
 178. The compound of anyone of claims 171 to 173, wherein J is optionally substituted C₂-C₉heterocyclylene or optionally substituted C₂-C₉ heteroarylene.
 179. Thecompound of claim 178, wherein the structure of Formula AA has thestructure of Formula AA3:

or a pharmaceutically acceptable salt thereof.
 180. The compound ofclaim 178, wherein the structure of Formula AA has the structure ofFormula A:

wherein in Y¹ is

R^(A5) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl; R^(A6) is H or optionally substitutedC₁-C₆ alkyl; and R^(A7) is H or optionally substituted C₁-C₆ alkyl; orR^(A6) and R^(A7), together with the carbon atom to which each is bound,combine to form optionally substituted C₃-C₆ carbocyclyl or optionallysubstituted C₂-C₅ heterocyclyl; or R^(A6) and R^(A7), together with thecarbon atom to which each is bound, combine to form optionallysubstituted C₃-C₆ carbocyclyl or optionally substituted C₂-C₅heterocyclyl; R^(A8) is H, optionally substituted C₁-C₆ alkyl, oroptionally substituted C₁-C₆ heteroalkyl; each of R^(A1), R^(A2),R^(A3), and R^(A4) is, independently, H, A², halogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl,optionally substituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₂-C₉ heteroaryl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ heteroalkenyl, optionally substituted —O—C₃-C₆carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or R^(A1)and R^(A2), R^(A2) and R^(A3), and/or R^(A3) and R^(A4), together withthe carbon atoms to which each is attached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A², whereinone of R^(A1), R^(A2), R^(A3), and R^(A4) is A², or

is substituted with A², or a pharmaceutically acceptable salt thereof.181. The compound of claim 180, each of R^(A1), R^(A2), R^(A3), andR^(A4) is, independently, H, A², halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxyl, thiol, or optionally substituted amino;or R^(A1) and R^(A2), R^(A2) and R^(A3), and/or R^(A3) and R^(A4),together with the carbon atoms to which each is attached, combine toform

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A², whereinone of R^(A1), R^(A2), R^(A3), and R^(A4) is A², or

is substituted with A², or a pharmaceutically acceptable salt thereof.182. The compound of claim 181, wherein each of R^(A1), R^(A2), R^(A3),and R^(A4) is, H, A², halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, hydroxyl, optionally substituted amino; or R^(A1)and R^(A2), R^(A2) and R^(A3), or R^(A3) and R^(A4), together with thecarbon atoms to which each is attached, combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², wherein one of R^(A1), R^(A2), R^(A3), and R^(A4)is A², or

is substituted with A².
 183. The compound of claim 182, wherein each ofR^(A1), R^(A2), R^(A3), and R^(A4) is, independently, H, A², F,

or R^(A1) and R^(A2), R^(A2) and R^(A3), or R^(A3) and R^(A4), togetherwith the carbon atoms to which each is attached, combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², wherein one of R^(A1), R^(A2), R^(A3), and R^(A4)is A², or

is substituted with A².
 184. The compound of any one of claims 180 to183, wherein Y¹ is


185. The compound of claim 184, wherein Y¹ is


186. The compound of claim 184, wherein Y¹ is


187. The compound of claim 186, wherein Y¹ is


188. The compound of claim 187, wherein Y¹ is


189. The compound of any one of claims 180 to 188, wherein the structureof Formula A has the structure of Formula A1:

or a pharmaceutically acceptable salt thereof.
 190. The compound of anyone of claims 180 to 188 wherein the structure of Formula A has thestructure of Formula A2:

or a pharmaceutically acceptable salt thereof.
 191. The compound of anyone of claims 180 to 188, wherein the structure of Formula A has thestructure of Formula A3:

or a pharmaceutically acceptable salt thereof.
 192. The compound of anyone of claims 180 to 188, wherein the structure of Formula A has thestructure of Formula A4:

or a pharmaceutically acceptable salt thereof.
 193. The compound of anyone of claims 180 to 188, wherein the structure of Formula A has thestructure of Formula A5:

or a pharmaceutically acceptable salt thereof.
 194. The compound of anyone of claims 180 to 188, wherein the structure of Formula A has thestructure of Formula A6:

or a pharmaceutically acceptable salt thereof.
 195. The compound of anyone of claims 180 to 188, wherein the structure of Formula A has thestructure of Formula A7:

or a pharmaceutically acceptable salt thereof.
 196. The compound of anyone of claims 180 to 188, wherein the structure of Formula A has thestructure of Formula A8:

or a pharmaceutically acceptable salt thereof.
 197. The compound of anyone of claims 180 to 188, wherein the structure of Formula A has thestructure of Formula A9:

or a pharmaceutically acceptable salt thereof.
 198. The compound of anyone of claims 180 to 188, wherein the structure of Formula A has thestructure of Formula A10:

or a pharmaceutically acceptable salt thereof.
 199. The compound of anyone of claims 180 to 198, wherein the structure of Formula A is

or derivative or analog thereof.
 200. The compound of claim 199, whereinthe structure of Formula A is


201. The compound of claim 200, wherein the structure of Formula A is

or derivative or analog thereof.
 202. The compound of any one of claims180 to 198, wherein

is

wherein R^(A9) is H, A², optionally substituted C₁-C₆ alkyl, oroptionally substituted C₁-C₆ heteroalkyl.
 203. The compound of claim202, wherein the structure of Formula A is


204. The compound of claim 203, wherein R^(A9) is H.
 205. The compoundof claim 203, wherein R^(A9) is A².
 206. The compound of claim 205,wherein the structure of Formula A is


207. The compound of claim 178, wherein the structure of Formula AA hasthe structure of Formula B:

wherein R^(A5) is H, optionally substituted C₁-C₆ alkyl, or optionallysubstituted C₁-C₆ heteroalkyl; each of R^(A1), R^(A2), R^(A3), andR^(A4) is, independently, H, A², halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, optionally substituted —O—C₃-C₆ carbocyclyl,hydroxyl, thiol, or optionally substituted amino; or R^(A1) and R^(A2),R^(A2) and R^(A3), and/or R^(A3) and R^(A4), together with the carbonatoms to which each is attached, combine to form

; and

is optionally substituted C₆-C₁₀ aryl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heteroaryl, or C₂-C₉heterocyclyl, any of which is optionally substituted with A², whereinone of R^(A1), R^(A2), R^(A3), and R^(A4) is A², or

is substituted with A², or a pharmaceutically acceptable salt thereof.208. The compound of claim 207, wherein each of R^(A1), R^(A2), R^(A3),and R^(A4) is, H, A², halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted—O—C₃-C₆ carbocyclyl, hydroxyl, optionally substituted amino; or R^(A1)and R^(A2), R^(A2) and R^(A3), or R^(A3) and R^(A4), together with thecarbon atoms to which each is attached, combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², wherein one of R^(A1), R^(A2), R^(A3), and R^(A4)is A², or

is substituted with A².
 209. The compound of claim 208, wherein each ofR^(A1), R^(A2), R^(A3), and R^(A4) is, independently, H, A², F,

or R^(A1) and R^(A2), R^(A2) and R^(A3), or R^(A3) and R^(A4), togetherwith the carbon atoms to which each is attached, combine to form

; and

is optionally substituted C₂-C₉ heterocyclyl, which is optionallysubstituted with A², wherein one of R^(A1), R^(A2), R^(A3), and R^(A4)is A², or

is substituted with A².
 210. The compound of any one of claims 207 to209, wherein the structure of Formula B has the structure of Formula B1:

or a pharmaceutically acceptable salt thereof.
 211. The compound of anyone of claims 207 to 209, wherein the structure of Formula B has thestructure of Formula B2:

or a pharmaceutically acceptable salt thereof.
 212. The compound of anyone of claims 207 to 209, wherein the structure of Formula B has thestructure of Formula B3:

or a pharmaceutically acceptable salt thereof.
 213. The compound of anyone of claims 207 to 209, wherein the structure of Formula B has thestructure of Formula B4:

or a pharmaceutically acceptable salt thereof.
 214. The compound of anyone of claims 207 to 209, wherein the structure of Formula B is


215. The compound of any one of claims 3 to 114, wherein the degradationmoiety comprises the structure of Formula C:

wherein R^(B1) is H, A², optionally substituted C₁-C₆ alkyl, oroptionally substituted C₁-C₆ heteroalkyl; R^(B2) is H, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₁-C₆ heteroalkyl;R^(B3) is A², optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₁-C₆ alkyl C₃-C₁₀carbocyclyl, or optionally substituted C₁-C₆ alkyl C₆-C₁₀ aryl; R^(B4)is H, optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or optionally substituted C₁-C₆ alkylC₆-C₁₀ aryl; R^(B5) is H, optionally substituted C₁-C₆ alkyl, oroptionally substituted C₁-C₆ heteroalkyl; v2 is 0, 1, 2, 3, or 4; eachR^(B6) is, independently, halogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and eachof R^(B7) and R^(B8) is, independently, H, halogen, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₆-C₁₀ aryl, whereinone of R^(B1) and R^(B3) is A², or a pharmaceutically acceptable saltthereof.
 216. The compound of claim 215, wherein the structure ofFormula C is

or derivative or analog thereof.
 217. The compound of any one of claims3 to 114, wherein the degradation moiety comprises the structure ofFormula D:

wherein A² is a bond between B and the linker; each of R^(C1), R^(C2),and R^(C7) is, independently, H, optionally substituted C₁-C₆ alkyl, oroptionally substituted C₁-C₆ heteroalkyl; R^(C3) is optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₁₀ carbocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₁-C₆ alkylC₃-C₁₀ carbocyclyl, or optionally substituted C₁-C₆ alkyl C₆-C₁₀ aryl;R^(C5) is optionally substituted C₁-C₆ alkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, or optionally substitutedC₁-C₆ alkyl C₆-C₁₀ aryl; v3 is 0, 1, 2, 3, or 4; each R^(C8) is,independently, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₁₀carbocyclyl, optionally substituted C₂-C₉ heterocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₂-C₉ heteroaryl,optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆heteroalkenyl, hydroxy, thiol, or optionally substituted amino; v4 is 0,1, 2, 3, or 4; and each R^(C9) is, independently, halogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl,optionally substituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₂-C₉ heteroaryl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ heteroalkenyl, hydroxy, thiol, or optionallysubstituted amino, or a pharmaceutically acceptable salt thereof. 218.The compound of claim 217, wherein the structure of Formula D is

or derivative or analog thereof.
 219. The compound of any one of claims3 to 114, wherein the degradation moiety comprises the structure ofFormula E:

wherein A² is a bond between B and the linker; each of R^(C10) andR^(C11) is, independently, H, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₁₀ carbocyclyl, optionally substituted C₆-C₁₀aryl, optionally substituted C₁-C₆ alkyl C₃-C₁₀ carbocyclyl, oroptionally substituted C₁-C₆ alkyl C₆-C₁₀ aryl; v5 is 0, 1, 2, 3, or 4;each R^(C12) is, independently, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, optionally substitutedC₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉ heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₂-C₉heteroaryl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ heteroalkenyl, hydroxy, thiol, or optionally substituted amino; v6is 0, 1, 2, 3, or 4; and each R²¹ is, independently, halogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl,optionally substituted C₃-C₁₀ carbocyclyl, optionally substituted C₂-C₉heterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₂-C₉ heteroaryl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ heteroalkenyl, hydroxy, thiol, or optionallysubstituted amino, or a pharmaceutically acceptable salt thereof. 220.The compound of claim 219, wherein the structure of Formula E is

or derivative or analog thereof.
 221. The compound of any one of claims3 to 114, wherein the degradation moiety comprises the structure ofFormula FA:

where

or a bicyclic moiety which is substituted with A² and substituted withone or more groups independently selected from H, R^(FF1), and oxo;

is a single bond or a double bond; u2 is 0, 1, 2, or 3; A² is a bondbetween the degrader and the linker; Y^(Fa) is CR^(Fb)R^(Fc), C═O, C═S,C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl,P(O)OH, P(O)NH₂; Y^(Fb) is NH, NR^(FF1), CH₂, CHR^(FF1), C(R^(FF1))₂, O,or S; Y^(Fc) is CR^(Fd)R^(Fe), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂; each of R^(Fb),R^(Fc), R^(Fd), and R^(Fe) is, independently, H, alkyl, aliphatic,heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxyl, alkoxy, amino,—NHalkyl, or —Nalkyl₂; or R^(Fb) and R^(Fc), together with the carbonatom to which each is attached, combine to form a 3-, 4-, 5-, or6-membered spirocarbocyclylene, or a 4-, 5-, or 6-memberedspiroheterocyclylene comprising 1 or 2 heteroatoms selected from N andO; or R^(Fd) and R^(Fe), together with the carbon atom to which each isattached, combine to form a 3-, 4-, 5-, or 6-memberedspirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylenecomprising 1 or 2 heteroatoms selected from N and O; and or R^(Fd) andR^(Fb), together with the carbon atoms to which each is attached,combine to form a 1, 2, 3, or 4 carbon bridged ring; each of Y^(Fd) andY^(Ff) is, independently, CH₂, CHR^(FF2), C(R^(FF2))₂, C(O), N, NH,NR^(FF3), O, S, or S(O); Y^(Fe) is a bond or a divalent moiety attachedto Y^(Fd) and Y^(Ff) that contains 1 to 5 contiguous carbon atoms thatform a 3 to 8-membered ring, wherein 1, 2, or 3 carbon atoms can bereplaced with a nitrogen, oxygen, or sulfur atom; wherein one of thering atoms is substituted with A² and the others are substituted withone or more groups independently selected from H and R^(FF1); andwherein the contiguous atoms of Y^(Fe) can be attached through a singleor double bond; each R^(FF1) is, independently, H, alkyl, alkenyl,alkynyl, aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxyl,amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl, alkylamino,alkylhydroxyl, or haloalkyl; each R^(FF2) is, independently, alkyl,alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H,—C(O)OH, —C(O)(aliphatic, including alkyl), —C(O)O(aliphatic, includingalkyl), —NH(aliphatic, including alkyl), —N(aliphatic includingalkyl)(aliphatic including alkyl), —NHSO₂alkyl, —N(alkyl)SO₂alkyl,—NHSO₂aryl, —N(alkyl)SO₂aryl, —NHSO₂alkenyl, —N(alkyl)SO₂alkenyl,—NHSO₂alkynyl, —N(alkyl)SO₂alkynyl, aliphatic, heteroaliphatic, aryl,heteroaryl, hetercyclic, carbocyclic, cyano, nitro, nitroso, —SH,—Salkyl, or haloalkyl; and R^(FF3) is alkyl, alkenyl, alkynyl, —C(O)H,—C(O)OH, —C(O)alkyl, or —C(O)Oalkyl, wherein if Y^(Fd) or Y^(Ff) issubstituted with A², then Y^(Fe) is a bond, or a pharmaceuticallyacceptable salt thereof.
 222. The compound of any one of claims 3 to114, wherein the degradation moiety comprises the structure of FormulaFB:

where

or a bicyclic moiety which is substituted with A² and substituted withone or more groups independently selected from H, R^(FF1), and oxo; A²is a bond between the degrader and the linker; Y^(Fa) is CR^(Fb)R^(Fc),C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)₂,P(O)alkyl, P(O)OH, P(O)NH₂; each of Y^(Fb) and Y^(Fg) is, independently,NH, NR^(FF1), CH₂, CHR^(FF1), C(R^(FF1))₂, O, or S; Y^(Fc) isCR^(Fd)R^(Fe), C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl, P(O)NHalkyl,P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂; each of R^(Fb), R^(Fc),R^(Fd), R^(Fe), R^(Ff), and R^(Fg) is, independently, H, alkyl,aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxyl,alkoxy, amino, —NHalkyl, or —Nalkyl₂; or R^(Fb) and RFC, together withthe carbon atom to which each is attached, combine to form a 3-, 4-, 5-,or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-memberedspiroheterocyclylene comprising 1 or 2 heteroatoms selected from N andO; or R^(Fd) and R^(Fe), together with the carbon atom to which each isattached, combine to form a 3-, 4-, 5-, or 6-memberedspirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylenecomprising 1 or 2 heteroatoms selected from N and O; or R^(Ff) andR^(Fg), together with the carbon atom to which each is attached, combineto form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selectedfrom N and O; or R^(Fd) and R^(Fb), together with the carbon atoms towhich each is attached, combine to form a 1, 2, 3, or 4 carbon bridgedring; or R^(Fd) and R^(Ff), together with the carbon atoms to which eachis attached, combine to form a 1, 2, 3, or 4 carbon bridged ring; orR^(Fb) and R^(Fg), together with the carbon atoms to which each isattached, combine to form a 1, 2, 3, or 4 carbon bridged ring; each ofY^(Fd) and Y^(Ff) is, independently, CH₂, CHR^(FF2), C(R^(FF2))₂, C(O),N, NH, NR^(FF3), O, S, or S(O); Y^(Fe) is a bond or a divalent moietyattached to Y^(Fd) and Y^(Ff) that contains 1 to 5 contiguous carbonatoms that form a 3 to 8-membered ring, wherein 1, 2, or 3 carbon atomscan be replaced with a nitrogen, oxygen, or sulfur atom; wherein one ofthe ring atoms is substituted with A² and the others are substitutedwith one or more groups independently selected from H and R^(FF1); andwherein the contiguous atoms of Y^(Fe) can be attached through a singleor double bond; each R^(FF1) is, independently, H, alkyl, alkenyl,alkynyl, aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxyl,amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl, alkylamino,alkylhydroxyl, or haloalkyl; each R^(FF2) is, independently, alkyl,alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H,—C(O)OH, —C(O)(aliphatic, including alkyl), —C(O)O(aliphatic, includingalkyl), —NH(aliphatic, including alkyl), —N(aliphatic includingalkyl)(aliphatic including alkyl), —NHSO₂alkyl, —N(alkyl)SO₂alkyl,—NHSO₂aryl, —N(alkyl)SO₂aryl, —NHSO₂alkenyl, —N(alkyl)SO₂alkenyl,—NHSO₂alkynyl, —N(alkyl)SO₂alkynyl, aliphatic, heteroaliphatic, aryl,heteroaryl, hetercyclic, carbocyclic, cyano, nitro, nitroso, —SH,—Salkyl, or haloalkyl; and R^(FF3) is alkyl, alkenyl, alkynyl, —C(O)H,—C(O)OH, —C(O)alkyl, or —C(O)Oalkyl, wherein if Y^(Fd) or Y^(Ff) issubstituted with A², then Y^(Fe) is a bond, or a pharmaceuticallyacceptable salt thereof.
 223. The compound of any one of claims 3 to114, wherein the degradation moiety comprises the structure of FormulaF1:

wherein A² is a bond between the degrader and the linker; and R^(F1) isabsent or O, or a pharmaceutically acceptable salt thereof.
 224. Thecompound of any one of claims 3 to 114, wherein the degradation moietycomprises the structure of Formula F2:

wherein A² is a bond between the degrader and the linker; and R^(F1) isabsent or O, or a pharmaceutically acceptable salt thereof.
 225. Thecompound of any one of claims 3 to 114, wherein the degradation moietycomprises the structure of Formula G:

wherein A² is a bond between the degrader and the linker; and R^(F1) isabsent or O, or a pharmaceutically acceptable salt thereof.
 226. Thecompound of any one of claims 3 to 225, wherein the linker has thestructure of Formula IV:A¹-(B¹)_(f)-(C¹)_(g)-(B²)_(h)-(D)-(B³)_(i)-(C²)_(j)-(B⁴)_(k)-A²  Formula IV wherein A¹ is a bond between the linker and A; A² is a bondbetween B and the linker; each of B¹, B², B³, and B⁴ is, independently,optionally substituted C₁-C₂ alkyl, optionally substituted C₁-C₃heteroalkyl, O, S, S(O)₂, or NR^(N); each R^(N) is, independently, H,optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl,optionally substituted C₂₋₄ alkynyl, optionally substituted C₂₋₆heterocyclyl, optionally substituted C₆₋₁₂ aryl, or optionallysubstituted C₁₋₇ heteroalkyl; each of C¹ and C² is, independently,carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; each of f, g, h, i, j,and k is, independently, 0 or 1; and D is optionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀ alkenyl, optionally substitutedC₂₋₁₀ alkynyl, optionally substituted C₂₋₆ heterocyclyl, optionallysubstituted C₆₋₁₂ aryl, optionally substituted C₂-C₁₀ polyethyleneglycol, or optionally substituted C₁₋₁₀ heteroalkyl, or a chemical bondlinking A¹-(B¹)_(f)-(C¹)_(g)-(B²)_(h)- to-(B³)_(i)-(C²)_(j)-(B⁴)_(k)-A².
 227. The method of claim 226, whereineach of B¹, B², B³, and B⁴ is, independently, optionally substitutedC₁-C₄ alkyl, optionally substituted C₁-C₄ heteroalkyl, or NR^(N). 228.The method of claim 226 or 227, wherein each R^(N) is, independently, Hor optionally substituted C₁-C₄ alkyl.
 229. The method of any one ofclaims 226 to 228, wherein each R^(N) is, independently, H or methyl.230. The compound of any one of claims 226 to 229, wherein each of B¹and B⁴ is, independently,


231. The compound of claim 230 wherein B¹ is


232. The compound of any one of claims 226 to 229, wherein each of C¹and C² is, independently,


233. The compound of claim 232, wherein C¹ is


234. The compound of any one of claims 226 to 233, wherein B² is NR^(N).235. The compound of any one of claims 226 to 233, wherein B² isoptionally substituted C₁-C₄ alkyl.
 236. The compound of any one ofclaims 226 to 235, wherein f is
 0. 237. The compound of any one ofclaims 226 to 235, wherein f is
 1. 238. The compound of any one ofclaims 226 to 237, wherein g is
 1. 239. The compound of any one ofclaims 226 to 238, wherein h is
 0. 240. The compound of any one ofclaims 226 to 238, wherein h is
 1. 241. The compound of any one ofclaims 226 to 240, wherein i is
 0. 242. The compound of any one ofclaims 226 to 241, wherein j is
 0. 243. The compound of any one ofclaims 226 to 242, wherein k is
 0. 244. The compound of any one ofclaims 226 to 243, wherein the linker has the structure of

wherein x is 1, 2, 3, 4, 5, 6, 7, or 8; y is 1, 2, 3, or 4; R^(x) is H,optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl; R^(y) is H,optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl; and W is O orNR^(w), wherein R^(w) is H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ heteroalkyl, or optionally substitutedC₃-C₆ carbocyclyl.
 245. The compound of any one of claims 226 to 244,wherein the linker has the structure of:


246. The compound of any one of claims 226 to 245, wherein the linkerhas the structure of


247. The compound of any one of claims 3 to 225, wherein the linker hasthe structure of Formula V:A¹-(E¹)-(F¹)—(C³)_(m)-(E³)_(n)-(F²)_(o1)-(F³)_(o2)-(E²)_(p)-A²,  Formula V wherein A¹ is a bond between the linker and A; A² is a bondbetween B and the linker; each of m, n, o1, o2, and p is, independently,0 or 1; each of E¹ and E² is, independently, O, S, NR^(N), optionallysubstituted C₁₋₁₀ alkylene, optionally substituted C₂₋₁₀ alkenylene,optionally substituted C₂₋₁₀ alkynylene, optionally substituted C₂-C₁₀polyethylene glycol, or optionally substituted C₁₋₁₀ heteroalkylene; E³is optionally substituted C₁-C₆ alkylene, optionally substituted C₁-C₆heteroalkylene, O, S, or NR^(N); each R^(N) is, independently, H,optionally substituted C₁₋₄ alkyl, optionally substituted C₂₋₄ alkenyl,optionally substituted C₂₋₄ alkynyl, optionally substituted C₂₋₆heterocyclyl, optionally substituted C₆₋₁₂ aryl, or optionallysubstituted C₁₋₇ heteroalkyl; C³ is carbonyl, thiocarbonyl, sulphonyl,or phosphoryl; and each of F¹, F², and F³ is, independently, optionallysubstituted C₃-C₁₀ carbocyclylene, optionally substituted C₂₋₁₀heterocyclylene, optionally substituted C₆-C₁₀ arylene, or optionallysubstituted C₂-C₉ heteroarylene.
 248. The compound of claim 247, whereinthe linker has the structure of Formula Va:A¹-(E¹)-(F¹)—(C³)_(m)-(E²)_(p)-A².   Formula Va
 249. The compound ofclaim 247, wherein the linker has the structure of Formula Vb:A¹-(E¹)-(F¹)-(E²)_(p)-A².   Formula Vb
 250. The compound of claim 247,wherein the linker has the structure of Formula Vc:A¹-(E¹)-(F¹)-A².   Formula Vc
 251. The compound of claim 247, whereinthe linker has the structure of Formula Vd:A¹-(E¹)-(F¹)—(C³)_(m)-(F²)_(o1)-A².   Formula Vd
 252. The compound ofclaim 247, wherein the linker has the structure of Formula Ve:A¹-(E¹)-(F¹)-(E³)_(n)-(F²)_(o1)-(E²)_(p)-A².   Formula Ve
 253. Thecompound of claim 247, wherein the linker has the structure of FormulaVf:A¹-(E¹)-(F¹)-(C³)_(m)-(E³)_(n)-(F²)_(o1)-(E²)_(p)-A².   Formula Vf 254.The compound of claim 247, wherein the linker has the structure ofFormula Vg:A¹-(E¹)-(F¹)-(E³)_(n)-(F²)_(o1)-A²,   Formula Vg
 255. The compound ofany one of claims 247 to 254, wherein each of E¹ and E² is,independently, NR^(N), optionally substituted C₁₋₁₀ alkylene, optionallysubstituted C₂-C₁₀ polyethylene glycolene, or optionally substitutedC₁₋₁₀ heteroalkylene.
 256. The compound of any one of claims 247 to 255,wherein E³ is optionally substituted C₁-C₆ alkylene, O, S, or NR^(N).257. The compound of claim 256, wherein E³ is optionally substitutedC₁-C₆ alkylene.
 258. The compound of claim 256, wherein E³ is optionallysubstituted C₁-C₃ alkylene.
 259. The compound of claim 256, wherein E³is a

where a is 0, 1, 2, 3, 4, or
 5. 260. The compound of claim 256, whereinE³ is


261. The compound of claim 256, wherein E³ is O.
 262. The compound ofany one of claims 247 to 261, wherein each R^(N) is, independently, H oroptionally substituted C₁₋₄ alkyl.
 263. The compound of claim 262,wherein each R^(N) is, independently, H or methyl.
 264. The compound ofany one of claims 247 to 263, wherein E¹ is

where a is 0, 1, 2, 3, 4, or
 5. 265. The compound of claim 264, whereinE¹ is


266. The compound of claim 265, wherein E¹ is


267. The compound of any one of claims 247 to 266, wherein E¹ is

wherein b is 0, 1, 2, 3, 4, 5, or 6; R^(a) is H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₆ carbocyclyl; R^(b) is H, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₆ carbocyclyl; and R^(c) is H, optionally substitutedC₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, or optionallysubstituted C₃-C₆ carbocyclyl.
 268. The compound of claim 267, whereinE¹ is


269. The compound of claim 268, wherein E¹ is


270. The compound of claim 267, wherein E¹ is


271. The compound of claim 270, wherein E¹ is


272. The compound of any one of claims 267 to 271, wherein Ra is H ormethyl.
 273. The compound of claim 272, wherein R^(a) is H.
 274. Thecompound of claim 272, wherein R^(a) is methyl.
 275. The compound of anyone of claims 247 to 274, wherein E² is O, NR^(w),

wherein c is 0, 1, 2, 3, 4, 5, 6, 7, or 8; d is 0, 1, 2, or 3; e is 0,1, 2, 3, 4, 5, or 6; f is 0, 1, 2, 3, or 4; R^(d) is H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₆ carbocyclyl; R^(e) is H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₆ carbocyclyl; R^(f) is H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₆ carbocyclyl; R^(g) is H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₁-C₆ heteroalkyl, oroptionally substituted C₃-C₆ carbocyclyl; and W is O or NR^(w), whereinR^(w) is H or optionally substituted C₁-C₆ alkyl.
 276. The compound ofclaim 275, wherein E² is O,


277. The compound of any one of claims 247 to 276, wherein each of F¹,F², or F³ is, independently, optionally substituted C₃-C₁₀carbocyclylene.
 278. The compound of claim 277, wherein the C₃-C₁₀carbocyclylene is monocyclic.
 279. The compound of claim 277, whereinthe C₃-C₁₀ carbocyclylene is polycyclic.
 280. The compound of claim 279,wherein the C₃-C₁₀ carbocyclylene is fused.
 281. The compound of claim279, wherein the C₃-C₁₀ carbocyclylene is spirocyclic.
 282. The compoundof claim 279, wherein the C₃-C₁₀ carbocyclylene is bridged.
 283. Thecompound of claim 282, wherein the C₃-C₁₀ carbocyclylene is


284. The compound of claim 283, wherein the C₃-C₁₀ carbocyclylene is


285. The compound of any one of claims 247 to 276, wherein each of F¹,F², or F³ is, independently, optionally substituted C₂-C₆heterocyclylene.
 286. The compound of claim 285, wherein the C₂-C₆heterocyclylene is monocyclic.
 287. The compound of claim 286, whereinthe C₂-C₆ heterocyclylene is

wherein q1 is 0, 1, 2, 3, or 4; q2 is 0, 1, 2, 3, 4, 5, or 6; q3 is 0,1, 2, 3, 4, 5, 6, 7, or 8; each R^(h) is, independently, ²H, halogen,optionally substituted C₁-C₆ alkyl, OR^(i2), or NR^(i3)R^(i4); or twoR^(h) groups, together with the carbon atom to which each is attached,combine to form optionally substituted C₃-C₁₀ carbocyclyl or optionallysubstituted C₂-C₉ heterocyclyl; or two R^(h) groups, together with thecarbon atoms to which each is attached, combine to form optionallysubstituted C₃-C₁₀ carbocyclyl or optionally substituted C₂-C₉heterocyclyl; R^(i1) is H or optionally substituted C₁-C₆ alkyl; R^(i2)is H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆heteroalkyl, or optionally substituted C₃-C₆ carbocyclyl;
 288. Thecompound of claim 287, wherein the C₂-C₉ heterocyclylene is


289. The compound of claim 287 or 288, wherein each R^(h) is,independently, ²H, halogen, cyano, optionally substituted C₁-C₆ alkyl,OR^(i2), or NR^(i3)R^(i4).
 290. The compound of claim 289, wherein eachRh ²H, F, methyl,


291. The compound of claim 290, wherein each R^(h) is, independently, F,methyl, or NR^(i3)R^(i4).
 292. The compound of any one of claims 287 to291, wherein q1 is 0, 1, or
 2. 293. The compound of any one of claims287 to 292, wherein q2 is 0, 1, or
 2. 294. The compound of any one ofclaims 287 to 293, wherein q3 is 0, 1, or
 2. 295. The compound of anyone of claims 287 to 294, wherein the C₂-C₉ heterocyclylene is


296. The compound of claim 295, wherein the C₂-C₉ heterocyclylene is


297. The compound of claim 296, wherein the C₂-C₉ heterocyclylene is


298. The compound of any one of claims 287 to 297, wherein F¹ is


299. The compound of any one of claims 287 to 298, wherein F² is


300. The compound of any one of claims 287 to 298, wherein F³ is


301. The compound of claim 285, wherein the C₂-C₆ heterocyclylene ispolycyclic.
 302. The compound of claim 301, wherein the C₂-C₆heterocyclylene is bicyclic.
 303. The compound of claim 301 or 302,wherein the C₂-C₆ heterocyclylene is bridged.
 304. The compound of claim303, wherein the C₂-C₆ heterocyclylene is


305. The compound of claim 301 or 302, wherein the C₂-C₆ heterocyclyleneis fused.
 306. The compound of claim 305, wherein the C₂-C₉heterocyclylene is


307. The compound of claim 306, wherein F¹ is


308. The compound of claim 306 or 307, wherein F² is


309. The compound of claim 301 or 302, wherein the C₂-C₆ heterocyclyleneis spirocyclic.
 310. The compound of claim 309, wherein the C₂-C₆heterocyclylene is


311. The compound of claim 310, wherein F¹ is


312. The compound of claim 310 or 311, wherein F² is


313. The compound of any one of claims 310 to 312, wherein F³ is


314. The compound of any one of claims 285 to 313 wherein the C₂-C₉heterocyclylene comprises a quaternary amine.
 315. The compound of anyone of claims 247 to 276, wherein each of F¹, F², or F³ is,independently, optionally substituted C₆-C₁₀ arylene.
 316. The compoundof claim 315, wherein the C₆-C₁₀ arylene is


317. The compound of any one of claims 247 to 276, wherein each of F¹,F², or F³ is, independently, optionally substituted C₂-C₉ heteroarylene.318. The compound of claim 317, wherein the C₂-C₉ heteroarylene is


319. The compound of claim 318, wherein F² is


320. The compound of claim 319, wherein F² is


321. The compound of any one of claims 247 to 320, C³ is


322. The compound of claim 321, wherein C³ is


323. The compound of any one of claims 247 to 322, wherein m is
 1. 324.The compound of any one of claims 247 to 322, wherein m is
 0. 325. Thecompound of any one of claims 247 to 324, wherein p is
 1. 326. Thecompound of any one of claims 247 to 324, wherein p is
 0. 327. Thecompound of any one of claims 247 to 326, wherein o1 is
 1. 328. Thecompound of any one of claims 247 to 326, wherein o1 is
 0. 329. Thecompound of any one of claims 247 to 328, wherein o2 is
 1. 330. Thecompound of any one of claims 247 to 328, wherein o2 is
 0. 331. Thecompound of any one of claims 247 to 330, wherein n is
 1. 332. Thecompound of any one of claims 247 to 330, wherein n is
 0. 333. Thecompound of any one of claims 247 to 332, wherein the linker has thestructure of


334. The compound of any one of claims 247 to 332, wherein the linkerhas the structure of


335. The compound of any one of claims 247 to 332, wherein the linkerhas the structure of:


336. The compound of any one of claims 3 to 225, wherein the linker isoptionally substituted C₃-C₁₀ carbocyclylene, optionally substitutedC₂₋₁₀ heterocyclylene, optionally substituted C₆-C₁₀ arylene, oroptionally substituted C₂-C₉ heteroarylene.
 337. The compound of claim336, wherein the linker is optionally substituted C₂₋₁₀ heterocyclylene338. The compound of claim 337, wherein the linker has the structure of


339. The compound of claim 338, wherein the linker has the structure of


340. The compound of any one of claims 3 to 225, wherein the linker isabsent.
 341. The compound of claim 1, wherein the compound has thestructure of any one of compounds B1-B6 in Table 1, or apharmaceutically acceptable salt thereof.
 342. The compound of any oneof claims 3 to 340, wherein the compound has the structure of any one ofcompounds D1-D31 in Table 2A, or a pharmaceutically acceptable saltthereof.
 343. The compound of any one of claims 3 to 340, wherein thecompound has the structure of any one of compounds D32-D211 in Table 2B,or a pharmaceutically acceptable salt thereof.
 344. The compound of anyone of claims 3 to 340, wherein the compound has the structure of anyone of compounds D212-D343 in Table 2C, or a pharmaceutically acceptablesalt thereof.
 345. A pharmaceutical composition comprising the compoundof any one of claims 1 to 344 and a pharmaceutically acceptableexcipient.
 346. A method of inhibiting the level of BRD9 in a cell, themethod involving contacting the cell with an effective amount of acompound of any one of claims 1 to 344, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition of claim
 345. 347. Amethod of inhibiting the activity of BRD9 in a cell, the methodinvolving contacting the cell with an effective amount of a compound ofany one of claims 1 to 344, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition of claim
 345. 348. The methodof claim 346 or 347, wherein the cell is a cancer cell.
 349. The methodof claim 348, wherein the cancer is a malignant, rhabdoid tumor, a CD8+T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladdercancer, stomach cancer, pancreatic cancer, esophageal cancer, prostatecancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma,non-small cell lung cancer, stomach cancer, or breast cancer.
 350. Themethod of claim 349, wherein the cancer is a sarcoma.
 351. The method ofclaim 350, wherein the sarcoma is a soft tissue sarcoma, synovialsarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adultfibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cellsarcoma, desmoplastic small round cell tumor, epithelioid sarcoma,fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma,liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheralnerve sheath tumors, myxofibrosarcoma, or low-grade rhabdomyosarcoma.352. The method of claim 351, wherein the sarcoma is synovial sarcoma.353. A method of treating a BAF complex-related disorder in a subject inneed thereof, the method involving administering to the subject aneffective amount of a compound of any one of claims 1 to 344, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of claim
 345. 354. A method of treating an SS18-SSX fusionprotein-related disorder in a subject in need thereof, the methodinvolving administering to the subject an effective amount of a compoundof any one of claims 1 to 344, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition of claim
 345. 355. A method oftreating a BRD9-related disorder in a subject in need thereof, themethod involving administering to the subject an effective amount of acompound of any one of claims 1 to 344, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition of claim
 345. 356. Themethod of any one of claims 353 to 355, wherein the disorder is cancer.357. A method of treating a cancer in a subject in need thereof, themethod including administering to the subject an effective amount of acompound of any one of claims 1 to 344, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition of claim
 345. 358. Themethod of claim 356 or 357, wherein the cancer is a malignant, rhabdoidtumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma,bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer,prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, asarcoma, non-small cell lung cancer, stomach cancer, or breast cancer.359. The method of claim 358, wherein the cancer is a sarcoma.
 360. Themethod of claim 359, wherein the sarcoma is a soft tissue sarcoma,synovial sarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adultfibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cellsarcoma, desmoplastic small round cell tumor, epithelioid sarcoma,fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma,liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheralnerve sheath tumors, myxofibrosarcoma, or low-grade rhabdomyosarcoma.361. The method of claim 360, wherein the sarcoma is synovial sarcoma.362. The method of any one of claims 352 to 355, wherein the disorder isinfection.
 363. A method of treating infection in a subject in needthereof, the method comprising administering to the subject an effectiveamount of a compound of any one of claims 1 to 342, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of claim
 343. 364. The method of claim 362 or 363, whereinthe infection is viral infection.
 365. The method of claim 364, whereinthe viral infection is an infection with a virus of the Retroviridaefamily, Hepadnaviridae family, Flaviviridae family, Adenoviridae family,Herpesviridae family, Papillomaviridae family, Parvoviridae family,Polyomaviridae family, Paramyxoviridae family, or Togaviridae family.366. The method of claim 364 or 365, wherein the viral infection isCoffin Siris, Neurofibromatosis, or Multiple Meningioma.